Introduction

Fibromyalgia (FM) is a generalised chronic pain condition that is often accompanied by fatigue, sleep disturbance, and psychological and cognitive alterations . It is the prototypical form of a central sensitisation syndrome and prevalence studies show that it affects 2–4% of the population (approximately half a million Italians). It is more common among adult women, but may also affect men and children.

There are currently no instrumental tests or specific diagnostic markers, and the characteristic symptoms of the disease overlap those of many other conditions . However, it is becoming more manageable as a result of the use of more rational evidence-based pharmacological therapy and a growing awareness that therapy needs to go beyond pain. Many studies have found that patients with FM are less physically fit than control groups of the same age, gender and occupation . The functional limitations reported by patients include reduced exercise tolerance, fatigue, and pain exacerbations caused by the activities of daily living (ADL) , which means that non-pharmacological therapeutic strategies aimed at improving aerobic fitness, muscular strength and endurance may be important in reducing disease-related disabilities . The effective management of FM is complex and requires a multidisciplinary approach, and it has been shown that integrated treatment, including appropriate patient education, aerobic exercise and cognitive-behavioural therapy, is effective in alleviating symptoms.

Diagnosis

FM is usually diagnosed in clinical and observational research studies on the basis of 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 (TPs) revealed by applying pressure (4 kg/cm ² ) at pre-defined 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 disturbance, 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 disturbance 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 TPs and extend the definition of FM to include symptoms other than pain and provide a means of assessing their severity . Moreover, a diagnosis is made by combining the patient’s history with a physical examination and laboratory tests, and excluding or accounting for other causes of the symptoms attributed to FM . As FM overlaps a number of other medical conditions, ranging from rheumatoid arthritis and lupus to hepatitis C infection, treating physicians need to be carefully analytic in the general evaluation of all patients with suspected FM.

Diagnosis

FM is usually diagnosed in clinical and observational research studies on the basis of 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 (TPs) revealed by applying pressure (4 kg/cm ² ) at pre-defined 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 disturbance, 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 disturbance 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 TPs and extend the definition of FM to include symptoms other than pain and provide a means of assessing their severity . Moreover, a diagnosis is made by combining the patient’s history with a physical examination and laboratory tests, and excluding or accounting for other causes of the symptoms attributed to FM . As FM overlaps a number of other medical conditions, ranging from rheumatoid arthritis and lupus to hepatitis C infection, treating physicians need to be carefully analytic in the general evaluation of all patients with suspected FM.

Inter-disciplinary treatment

The aim of treating FM is to decrease pain and increase function by means of a multimodal therapeutic strategy which, in most cases, includes pharmacological and non-pharmacologic interventions and has the main goal of symptom management . As FM patients typically present 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, behavioural and educational strategies .

Most of the directors of multidisciplinary treatment programmes are rheumatologists or rehabilitation specialists, but there is no reason for excluding other health professionals. Some of the programmes mainly based on promoting cognitive-behavioural changes only involve rheumatologists and psychologists or psychiatrists, who are often considered essential because most FM patients have difficulties in dealing with stress and interpersonal problems, and are at increased risk of developing depression or anxiety . As exercise is a critical part of FM treatment and a key element in successful cognitive behavioural therapy, most programmes would benefit from the addition of an exercise physiologist or physical therapist with expertise in prescribing stretching, aerobic conditioning and strength training exercises . Other possible team members consultants are social workers, occupational therapists, sleep or headache specialists, or massage therapists .

Education and psychological domains

A number of the techniques used in the management of FM are based on patient education, and are intended to reduce anxiety, increase treatment compliance, improve coping behaviours and self-efficacy, and draw attention away from symptoms and towards improved function and a better quality of life. It has long been recognised that patients have an essential right to education, and the findings of this review suggest that they should be offered exercises and education (including information and cognitive-behavioural strategies) by a multidisciplinary team in a group format .

One of the aims of a multidisciplinary approach should be to switch patients’ perceptions from helplessness, frustration and sometimes anger, to a positive sense of behavioural self-efficacy and outcome expectancies . Self-efficacious patients are more likely to respond favourably to treatment programmes and experience better outcomes , whereas many patients believe that they cannot control their pain, disability or other negative effects (which leads to increased distress, pain and sleep difficulties), tend to take less part in daily living activities, and fail to develop effective coping behaviours and cognitions.

Psychological interventions involve the interrelationships between the physical and psychological aspects of the illness . Two major approaches are psychophysiologically-based therapy (PPT), such as electromyography (EMG) biofeedback, and cognitive-behavioural therapy (CBT). The basic aim of PPT is to change cognitions by manipulating physiological responses, whereas the aim of CBT is to change physiological responses by manipulating cognitions in order to help patients feel that they are in control .

CBT is a combination of cognitive and behavioural therapies, and may have a wide range of components. The behavioural components include a number of techniques centred on the core tenets of operant and classical psychological conditioning, and may be extended to methods such as relaxation, sleep hygiene, pacing activities, scheduling social and leisure opportunities, coping with pain, education, and training in assertiveness , all of which go to make up the CBT “toolbox.” This concept is important when considering CBT for FM patients because any meaningful discussion and evaluation must take into account the tools that are used.

Comorbidities such as stiffness, fatigue and problems with sleep, concentration and memory are more or less common in almost all FM patients. It is not surprising that many patients experience interpersonal distress and behavioural deficits and, as CBT is particularly effective in the case of distress and behavioural disorders, it is logical to apply it to FM. This approach assumes that a patient can be helped significantly by addressing the many non-pain aspects of FM.

Pharmacologic treatments

Once a diagnosis of FM is made, patients are usually started on pharmacological treatment. Boomershine and Crofford suggest that the three drugs currently approved by the American Food and Drugs Administration (FDA) should now be used as ‘anchor drugs’ and, although still important, could later be complemented by older approaches. Unfortunately, no direct comparative studies have yet been published, and there is still no consensus as to where to start.

FM patients experience amplified ascending sensory input; mediated by excess 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 system (DNIC), the descending pain regulation pathways which play an inhibitory role in pain perception and are mediated in part by the neurotransmitters serotonin and norepinephrine, can be treated using serotonin-norepinephrine re-uptake inhibitors (SNRIs). This may be an over-simplification, but it does show that there are at least two complementary symptom control strategies.

Pregabalin is an α ₂ -δ ligand that has analgesic, anxiolytic-like and anticonvulsant activity in animal models, and biochemical studies have found that the primary binding site for pregabalin and the related gabapentin is α ₂ -δ (type 1) . Alpha ₂ -delta is an auxiliary protein associated with voltage-gated calcium channels, and the potent binding of pregabalin at the α ₂ -δ site reduces calcium influx at nerve terminals resulting in reduction of the release of a number of neurochemicals, including glutamate, noradrenaline and substance P , which may explain the analgesic, anticonvulsant and anxiolytic-like activity of pregabalin in animal models. It has also been suggested that reducing neurotransmitter release from neurons in the spinal cord and brain may be clinically beneficial for FM patients.

Pregabalin is approved for the treatment of FM and neuropathic pain and, in some countries, also for the management of generalised anxiety disorder and as an adjuvant medication for seizures. The dose indicated for the treatment of FM is 300–450 mg/day divided into two administration, although many clinicians start with smaller nightly doses, as it seems to have a specific beneficial effect on sleep . Anxiety is also very common in FM patients and, as patients with concomitant sleep disorders and anxiety almost always experience initial insomnia, pregabalin is a rational choice. The dose can subsequently be increased to the recommended dose, but escalation may be limited by side effects such as weight gain, edema and dizziness that may resolve over time.

Although it is not approved by the FDA, the use of gabapentin has also been studied in FM patients , and daily doses ranging from 1200 mg to 2400 mg have been found to have some effect. Although the gabapentin trial involved far fewer patients than the pregabalin trials, the effect sizes seemed to be similar, and so gabapentin can be considered an option especially when pregabalin is not available.

The other two FDA-approved medications for the treatment of FM are duloxetine and milnacipran. Duloxetine is also FDA-approved for depression, generalised anxiety disorder, painful diabetic neuropathy, and most recently, chronic musculoskeletal pain. Milnacipran is also approved for the management of major depression in Europe and Japan . Both are SNRIs, and it has been hypothesised that pain, anxiety, chronic stress and depression have overlapping pathogenetic backgrounds (neurotransmitters and immune responses), and depression can be considered a systemic disease related to unbalanced neurotransmission also to other neurotrophic, neurosteroidal, central nervous system (CNS) hormonal modifications, and widespread autonomic, immunological and metabolic somatic changes . According to this hypothesis, antidepressants restore neurotransmitter levels and modulate receptor expression in the hypothalamus, which normalises hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis . Autonomic system alterations, such as sympathetic overactivity, are encountered in both depression and FM . Finally, pro-inflammatory cytokines inside the CNS play a role in the pathophysiology of mood disorders and pain, and their modulation by means of chronic antidepressant administration contributes to improving both .

The trials of duloxetine have shown that 70% of its effect on pain is due to its analgesic rather than its antidepressant action , although it is still is a good choice for patients with FM, depression and anxiety. The FM dose is 60 mg once a day, but it is usually started at a daily dose of 30 mg. Duloxetine seems to have a neutral effect on sleep.

The recommended milnacipran doses range from 50 mg twice a day to 100 mg twice a day. It has been found that it significantly improves fatigue and cognitive dysfunction, possibly because of its greater adrenergic effect .

Analgesic treatment

Tramadol has been found to be beneficial in FM patients . It is an atypical pain reliever that has a different action on the CNS (the re-uptake 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 given 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 . Its potential for drug abuse is fortunately negligible, but there is a theoretical risk of seizures and serotoninergic syndrome when it is combined with selective serotonin re-uptake inhibitors (SSRIs), SNRIs, monoamine oxidase inhibitors (MAOIs) and tryptans, although only a few cases have been described .

There is no scientific evidence that NSAIDs alone are effective in FM patients, although they may be useful for analgesia when combined with TCAs. However, the results obtained when NSAIDs are combined with benzodiazepines have been inconsistent . The CNS mechanisms of FM (central sensitisation and disinhibition, and a dysfunctional HPA axis) may explain the relatively reduced efficacy of NSAIDs and opioids, particularly as the latter are more effective for peripheral pain . However, NSAIDs can be helpful in reducing pain flares induced by excessive physical activity, tendinitis or bursitis, although they should only be used on an as needed basis in order to avoid side effects. COX ₂ inhibitors have much fewer side effects, but are less effective against pain.

One recent study has found that transdermal buprenorphine, a strong opioid, has beneficial effects on severe widespread pain (VAS >6/10), but it is less effective on the other symptoms typical 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 and so on, may receive a significant benefit .

The doses of immediate-release opioids should be increased slowly until the pain is reduced, and then the patients should be switched to controlled-release opioids.

Opioids may be helpful in treating FM-related pain, but they may also induce tolerance and become habit forming, and are also associated with adverse effects such as constipation, sedation and nausea . Physicians should obtain a careful medical and psychological profile of the patient before prescribing opioids.

Treating fatigue, sleep and mood disorders

Fatigue and sleep disturbances are major complaints among FM patients . Appropriate treatment of sleep disturbances and physical rehabilitation are the best means of managing fatigue in the long term. The medications commonly used in narcolepsy have been used to treat fatigue in FM patients . Modafinil has been approved by the FDA for the treatment of excessive somnolence associated with narcolepsy, shift workers and sleep apnea, and can be useful if fatigue prevents patients from starting physical rehabilitation. The initial dose is 50 mg in the morning, and can be increased to 400 mg daily, although modafinil and other compounds carry a risk of abuse and drug interactions.

Small doses of the amitriptyline or cyclobenzaprine represent the first approach to the treatment of delayed sleep onset in FM patients, but they are only effective in about 30% of cases and most patients cannot tolerate higher doses because of their sedative and cholinergic side effects . Although it has not been formally tested, trazodone is a usually well-tolerated sedating antidepressant. Hypnotic drugs such as zolpidem, zoplicone and eszoplicone can also be used, and act mainly through the BZ1 receptor. Benzodiazepines should be used cautiously as they may disrupt sleep architecture.

Sodium oxybate is the sodium salt of gamma-hydroxybutyrate (GHB), an endogenous short chain fatty acid, used for the oral administration of exogenous GHB . The supraphysiological concentrations induced by exogenous administration probably lead to qualitatively different neuronal activity from that of endogenous GHB. GHB may play a neuromodulating/neurotransmitting role, and sodium oxybate is approved by the FDA for the treatment of cataplexy and excessive daytime sleepiness. It has recently also been shown to improve pain and fatigue in phase III FM trials .

Thirty percent of FM patient suffer from depression at the time of diagnosis, and 50–60% sometimes during their lifetime . There is also evidence that anxiety can be as common as depression in FM patients, and post-traumatic stress disorder (PTSD) is more prevalent in FM patients than in the general population .

The central monoaminergic neurotransmission abnormalities observed in depression may play a role in FM pathophysiology because dysfunctioning 5-HT- and NE-mediated descending pain-inhibitory pathways are important mechanisms in FM-related pain. Antidepressants that increase 5-HT- and NE-mediated neurotransmission are frequently used to treat FM and other chronic pain conditions, particularly neuropathic pain. Inhibiting both 5-HT and NE re-uptake transporters using TCAs or SNRIs seems to be more effective in treating pain and FM than inhibiting either transporter alone with selective SSRIs or noradrenergic re-uptake inhibitors (NARIs) , but the efficacy of TCAs is counterbalanced by their side effects. SSRIs such as citalopram , escitalopram, paroxetine and sertraline are not effective against pain but. like fluoxetine, could be used to treat associated depression.