Fibromyalgia, Causes, Symptoms, Diagnosis, Treatment









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Fibromyalgia is a common condition characterized by abnormal central nervous system sensitivity to external stimuli. It affects between 2 and 8% of the total population, with a strong female predominance. The most recognizable clinical feature associated with fibromyalgia is widespread pain and tenderness throughout multiple regions of the body, in the absence of pathology at the sites of pain. Patients may also experience a wide variety of other symptoms including fatigue and sleep disturbance, cognitive changes such as poor concentration and memory, and amplified sensory systems leading to an intolerance of loud noise, bright lights, and strong odors. Medication side effects are commonly exacerbated in this patient population and many drugs are poorly tolerated. Fibromyalgia is associated with several related medical conditions including irritable bowel syndrome, temporomandibular joint dysfunction, tension headaches, chronic fatigue syndrome, and restless leg syndrome.

Fibromyalgia is a syndrome characterized by chronic widespread pain at multiple tender points, joint stiffness, and systemic symptoms (e.g., mood disorders, fatigue, cognitive dysfunction, and insomnia) [] without a well-defined underlying organic disease. Nevertheless, it can be associated with specific diseases such as rheumatic pathologies, psychiatric or neurological disorders, infections, and diabetes

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The pathophysiology of fibromyalgia is complex, although understanding has increased substantially in recent years. The net effect of multiple factors leads to a sensitization of central pain and sensory processing centers such that patients become overly sensitive to external stimuli. Functional imaging studies have shown amplified responses in sensory regions of the brain when mechanical or painful stimuli are administered. There is also evidence of enhanced connections between brain centers that process pain and sensory input, such as the insular cortex, and parts of the brain associated with concentration and working memory, such as the frontoparietal executive attention network. This may provide some explanation for the cognitive symptoms many patients experience. Several abnormalities of neurotransmitters have also been identified in fibromyalgia patients, and relate to the modulation of descending sensory inhibitory pathways from the brain to the spinal cord. These are discussed in relation to specific pharmacological interventions in later sections

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Fibromyalgia has a strong genetic predisposition — twin studies suggest the contribution is as high as 50%. In genetically susceptible individuals, symptoms tend to be triggered by a stressful event such as physical illness, trauma or psychological distress Symptoms of fibromyalgia wax and wane over time, and tend to be exacerbated by fluctuations in psychological or physical stress.

Diagnosis of fibromyalgia is based on the identification of characteristic clinical features. Validated diagnostic criteria are available and require the presence of widespread pain in conjunction with high levels of some of the above mentioned associated symptoms.

Causes of Fibromyalgia

  • Infections –  Prior illnesses may trigger fibromyalgia or make symptoms of the condition worse.
  • Genetics – Fibromyalgia often runs in families. If you have a family member with this condition, your risk for developing it is higher. Researchers think certain genetic mutations may play a role in this condition. Those genes haven’t yet been identified.
  • Trauma – People who experience physical or emotional trauma may develop fibromyalgia. The condition has been linked with post-traumatic stress disorder.
  • Stress – Like trauma, stress can create long-reaching effects your body deals with for months and years. Stress has been linked to hormonal disturbances that could contribute to fibromyalgia.
  • Viral infection – Viral infections such as the herpes simplex -1 virus, commonly linked to cold sores, have been connected to the development of fibromyalgia.
  • Dysfunctional pain processing – Many researchers agree that one of the key causes of fibromyalgia is dysfunction in the central nervous system’s (CNS) pain processing.
  • Having a family history of fibromyalgia
  • Repetitive injuries
  • Rheumatoid arthritis or other autoimmune diseases
  • Central nervous system (CNS) problems
  • The way our genes regulate how we process painful stimuli
  • Being exposed to stressful or traumatic events, such as
  • Car accidents
  • Injuries to the body caused by performing the same action over and over again (called “repetitive” injuries)
  • Infections or illnesses
  • Being sent to war

Symptoms of Fibromyalgia

Common symptoms include

  • widespread body-wide pain
  • jaw pain and stiffness
  • pain and tiredness in the face muscles and adjacent fibrous tissues
  • stiff joints and muscles in the morning
  • headaches
  • irregular sleep patterns
  • irritable bowel syndrome (IBS)
  • painful menstrual periods
  • tingling and numbness in the hands and feet
  • restless leg syndrome (RLS)
  • sensitivity to cold or heat
  • difficulties with memory and concentration are known as “fibro-fog”
  • fatigue

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The following are also possible:

  • problems with vision
  • nausea
  • pelvic and urinary problems
  • weight gain
  • dizziness
  • cold or flu-like symptoms
  • skin problems
  • chest symptoms
  • depression and anxiety
  • breathing problems
  • dizziness and clumsiness
  • feeling too hot or too cold – this is because you’re not able to regulate your body temperature properly
  • restless legs syndrome (an overwhelming urge to move your legs)
  • tingling, numbness, prickling or burning sensations in your hands and feet (pins and needles, also known as paraesthesia)
  • in women, unusually painful periods
  • anxiety
  • depression
  • Widespread muscle soreness
  • Muscle spasms
  • Tenderness
  • Headaches or migraines
  • Rebound pain
  • Irritable bowel syndrome
  • Nausea
  • Constipation
  • Excessive gas
  • Diarrhea
  • Painful bladder syndrome
  • Increased sensitivity to pain
  • Pins and needles sensations
  • Increased overall sensitivity to cold and touch
  • Forgetfulness
  • Inability to concentrate, or “fibro fog”
  • Problems with balance and coordination
  • Fatigue
  • Depression
  • Nervous energy
  • Anxiety
  • Emotional sensitivity
  • Increased stress response
  • Sleep disorders
  • Joint stiffness
  • Menstrual pain or changes
  • Increased chance of other health conditions

Diagnosis of Fibromyalgia 

Differential diagnosis

This includes:

  • inflammatory arthritis (IA) and spondylo-arthropathies,
  • autoimmune connective tissue disease,
  • myositis,
  • myopathies,
  • primary generalized osteoarthritis,
  • polymyalgia rheumatica,
  • hypothyroidism,
  • malignancies.

Laboratory Investigations

Laboratory testing, such as complete blood count, erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibody, thyroid-stimulating hormone, T3, T4, creatinine phosphokinase, a serum muscle enzyme, vitamin D, ESR, CRP, renal function, and liver function tests are necessary to rule out other disorders. X-rays, blood tests, specialized scans such as nuclear medicine and CT scan muscle biopsy are normal in cases of fibromyalgia.

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Differential diagnoses for fibromyalgia and corresponding diagnostic testing options.

Differential diagnosesDiagnostic testing options
  • Adrenal dysfunction
Morning serum cortisol, urinary catecholamine metabolites
  • Anemia
CBC with differential, RBC indices (MCV, MHC, MCHC)
  • Bone marrow disease
WBC differential, ESR, CRP, CMP
  • Chronic fatigue syndrome
Clinical history
  • Functional disorders (e.g., intestinal dysbiosis, subtle endocrine imbalances, and postviral immune suppression)
Standard laboratory testing yields unclear results
  • Hypothyroidism
Thyroid function tests (T3, T4, TSH)
  • Lyme disease
Lyme titer, CMP
  • Psychiatric conditions (e.g., PTSD, anxiety, and depression)
Refer to DSM-IV
  • Multiple sclerosis
MRI scan, lumbar puncture, evoked potential testing
  • Phenomenological referred myofascial pain
Muscular tender points on physical examination
  • Rheumatoid autoimmune disorders (e.g., rheumatoid arthritis, ankylosing spondylitis, and scleroderma)
Rheumatic profile (rheumatoid factor, ESR/CRP), ANA
  • Sleep disorders
EEG sleep studies
  • Spinal facet pain or sacroiliac joint pain
Radiologic studies (MRI scan, CT scan), bone scans (minimal diagnostic assistance)
  • Spinal disc herniation
MRI scan
  • Systemic inflammation or infection
Radiologic studies (MRI scan, CT scan), bone scans (minimal diagnostic assistance)
  • Vitamin and/or mineral deficiency
Radiologic studies (MRI scan, CT scan), bone scans (minimal diagnostic assistance)

 

The location of the nine paired tender points that comprise the 1990 American College of Rheumatologycriteria for fibromyalgia.

There is no single test that can fully diagnose fibromyalgia and there is debate over what should be considered essential diagnostic criteria and whether an objective diagnosis is possible. In most cases, people with fibromyalgia symptoms may also have laboratory test results that appear normal and many of their symptoms may mimic those of other rheumatic conditions such as arthritis or osteoporosis. The most widely accepted set of classification criteria for research purposes was elaborated in 1990 by the Multicenter Criteria Committee of the American College of Rheumatology. These criteria, which are known informally as “the ACR 1990”, define fibromyalgia according to the presence of the following criteria:

  • A history of widespread pain lasting more than three months – affecting all four quadrants of the body, i.e., both sides, and above and below the waist.
  • Tender points – there are 18 designated possible tender points (although a person with the disorder may feel pain in other areas as well). Diagnosis is no longer based on the number of tender points.

The ACR criteria for the classification of patients were originally established as inclusion criteria for research purposes and were not intended for clinical diagnosis but have now become the de facto diagnostic criteria in the clinical setting. It should be noted that the number of tender points that may be active at any one time may vary with time and circumstance. A controversial study was done by a legal team looking to prove their client’s disability based primarily on tender points and their widespread presence in non-litigious communities prompted the lead author of the ACR criteria to question now the useful validity of tender points in diagnosis. Use of control points has been used to cast doubt on whether a person has fibromyalgia, and to claim the person is malingering; however, no research has been done for the use of control points to diagnose fibromyalgia, and such diagnostic tests have been advised against, and people complaining of pain all over should still have fibromyalgia considered as a diagnosis.

2010 provisional criteria

Widespread Pain Index (WPI) Areas

In 2010, the American College of Rheumatology approved provisional revised diagnostic criteria for fibromyalgia that eliminated the 1990 criteria’s reliance on tender point testing. The revised criteria use a widespread pain index (WPI) and symptom severity scale (SS) in place of tender point testing under the 1990 criteria. The WPI counts up to 19 general body areas in which the person has experienced pain in the preceding two weeks. The SS rates the severity of the person’s fatigue, unrefreshed waking, cognitive symptoms, and general somatic symptoms, each on a scale from 0 to 3, for a composite score ranging from 0 to 12. The revised criteria for diagnosis are:

  • WPI ≥ 7 and SS ≥ 5 OR WPI 3–6 and SS ≥ 9,
  • Symptoms have been present at a similar level for at least three months, and
  • No other diagnosable disorder otherwise explains the pain.

Multidimensional assessment

Some research has suggested not to categorize fibromyalgia as a somatic disease or a mental disorder, but to use a multidimensional approach taking into consideration somatic symptoms, psychological factors, psychosocial stressors and subjective belief regarding fibromyalgia. A review has looked at self-report questionnaires assessing fibromyalgia on multiple dimensions, including:

  • Revised Fibromyalgia Impact Questionnaire
  • Widespread Pain Index
  • Hospital Anxiety and Depression Scale
  • Multiple Ability Self-Report Questionnaire
  • Multidimensional Fatigue Inventory
  • Medical Outcomes Study Sleep Scale

Fibromyalgia survey questionnaire

I. Using the following scale, indicate for each item the level of severity over the past week by checking the appropriate box.
0: No problem
1: Slight or mild problems; generally mild or intermittent
2: Moderate; considerable problems; often present and/or at a moderate level
3: Severe; continuous, life-disturbing problems
Fatigue□ 0 □ 1 □ 2 □ 3
Trouble thinking or remembering□ 0 □ 1 □ 2 □ 3
Waking up tired (unrefreshed)□ 0 □ 1 □ 2 □ 3
II. During the past 6 months have you had any of the following symptoms?
Pain or cramps in lower abdomen□ Yes □ No
Depression□ Yes □ No
Headache□ Yes □ No
III. Joint/body pain
Please indicate below if you have had pain or tenderness over the past 7 days in each of the areas listed below. Please make an X in the box if you have had pain or tenderness. Be sure to mark both right side and left side separately.
□ Shoulder, left□ Upper leg, left□ Lower back
□ Shoulder, right□ Upper leg, right□ Upper back
□ Hip, left□ Lower leg, left□ Neck
□ Hip, right□ Lower leg, right
□ Upper arm, left□ Jaw, left□ No pain in any of these areas
□ Upper arm, right□ Jaw, right
□ Lower arm, left□ Chest
□ Lower arm, right□ Abdomen
IV. Overall, were the symptoms listed in I–III above generally present for at least 3 months? □ Yes □ No
Source: Reference 

Treatment of fibromyalgia

Comparison between American Pain Society (APS) and Association of the Scientific Medical Societies in Germany (AWMF) with European League Against Rheumatism (EULAR).

Nonpharmacologic treatmentMedications
APS (American Pain Society) and AWMF (Association of the Scientific Medical Societies in Germany)Strong evidence:
Patient education
CBT
Aerobic exercise
Multidisciplinary therapy
Strong evidence:
Amitriptyline (25/50 mg)
NNT 3,54 (95% CI 2,74, 5,01)
Cyclobenzaprine (10/30 mg)
Moderate evidence:
Strength training
Acupuncture
Hypnotherapy
Biofeedback
Balneotherapy
Moderate evidence:
SNRIs:
Milnacipran (100 mg)
NNT 7.2 (95% CI 5.2, 11.4)
NNH 7.6 (95% CI 6.2, 9.9)
Duloxetine (60/120 mg)
NNT 19 (95% CI 7.4, 20.5)
NNH 14.9 (95% CI 9.1, 41.4)
SSRI:
Fluoxetine (20/80 mg)
Tramadol (200/300 mg)
Anticonvulsant:
Pregabalin (300/450 mg)
NNT 8.6 (95% CI 6.4, 12.9)
NNH 7.6 (95% CI 6.3, 9.4)
EULAR (European League Against Rheumatism)Balneotherapy (grade B)Tramadol (grade A)
Individually tailored exercise including aerobic and strength training (grade C)Analgesics (paracetamol/acetaminophen, weak opioids) (grade D)
Cognitive-behavioral therapy (grade B)Antidepressants (amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide, pirlindol) (grade A)
Others: relaxation, rehabilitation, physiotherapy, and/or psychological support (grade C)Tropisetron, pramipexole, pregabalin (grade A)

Fibromyalgia can have a substantial impact on both a patient’s mental and physical health. Low work participation, high rates of financial dependency and poor quality of life are all well described in this population Treatment of fibromyalgia is aimed at modulating central pain pathways to reduce sensitivity, which can be obtained via a range of treatment modalities. The most recently published guidelines are the 2016 European League Against Rheumatism (EULAR) fibromyalgia management guidelines, and the 2012 Canadian fibromyalgia diagnosis and management guidelines, and these are referred to and discussed in this article

The mainstay of treatment is non-pharmacological. Evidence-based treatment strategies with the highest efficacy include education in relation to the nature of the condition, graded exercise programmes, and psychological-based interventions. These may range from cognitive-based stress management therapy with a pain management psychologist to yoga, tai-chi or simple meditation strategies. These non-pharmacological interventions are recommended by EULAR as first-line treatments. More than 30 trials involving more than 2,000 fibromyalgia patients have been performed evaluating various forms of exercise, and a further 2,000 patients have been involved in trials of cognitive based therapy (CBT)Both aerobic and strengthening exercises have been shown to significantly reduce pain and increase function, with CBT also proving effective, albeit with lower quality evidence. The EULAR guidelines provide a thorough review of the evidence to support the various non-pharmacological strategies available.

However, many patients require the addition of pharmacological therapy for the management of their symptoms. It should be noted that medication is unlikely to be of benefit in isolation in the absence of the above-mentioned strategies.

Several medications have shown some efficacy in the management of fibromyalgia. Availability and condition-specific approval of medications vary across countries (see Table 1). There are currently no medications with fibromyalgia-specific approval under the European Medicines Agency, although many of the discussed agents are approved for other conditions. Many patients will respond to some degree to one or more of the discussed medications, although each individual medication is only effective in a minority of patients. Patients may need to trial several options before finding one that is both tolerable and helpful.

Table 1: Availability and approval of recommended medications for fibromyalgia 
*France, Portugal, Finland, Estonia, Austria, Luxembourg, Poland, Turkey, Bulgaria, and Russia.
EuropeUnited StatesAustraliaCanada
DrugAvailableApproved for fibromyalgiaAvailableApproved for fibromyalgiaAvailableApproved for fibromyalgiaAvailableApproved for fibromyalgia
AmitriptylineYesNoYesNoYesNoYesNo
CyclobenzaprineNoNoYesNoNoNoYesNo
DuloxetineYesNoYesYesYesNoYesYes
MilnacipranSome countries only*NoYesYesYesYesNoNo
PregabalinYesNoYesYesYesNoYesYes
TramadolYesNoYesNoYesNoYesNo

Neuromodulatory medications

These include the antidepressant (tricyclic, selective serotonin-norepinephrine uptake inhibitor (SNRI), serotonin selective reuptake inhibitor (SSRI)] and anticonvulsant classes of medications. Amitriptyline has some evidence and is recommended in all the guidelines,and, therefore, is worthwhile considering particularly for patients with FM and sleep disturbance. The serotonin-norepinephrine uptake inhibitors (SNRIs) have better evidence than SSRIs, and may benefit from their effect on both serotonin and noradrenaline on the descending modulatory pathways. Gabapentin and pregabalin are also commonly used in FM and CWP.

Serotonin and noradrenergic reuptake inhibitors (SNRIs)

Serotonin and noradrenaline are neurotransmitters involved in pain-processing pathways via their action on descending inhibitory pathways in the brain and spinal cord, with the net effect of reducing sensory input from the periphery. Both neurotransmitters have an array of other functions including roles in the regulation of mood and emotion, with noradrenaline also involved in the regulation of attention and memory

The cerebrospinal fluid (CSF) of patients with fibromyalgia has been shown to have lower levels of biogenic amines, the metabolites of noradrenaline and serotonin, suggesting a deficiency of these neurotransmitters. Studies using murine models have shown that modulation of noradrenaline and serotonin in unison provides more effective analgesic effects than modulation of serotonin alone. However, there is no direct comparative study between SNRIs and selective serotonin reuptake inhibitors (SSRIs) in fibromyalgia. Two SNRI medications, duloxetine, and milnacipran are recommended for the treatment of fibromyalgia. Milnacipran is not approved by the European Medicines Agency, but it is approved in several European countries for indications other than fibromyalgia, such as depression (see Table 1).

Duloxetine – is an SNRI originally marketed for the treatment of depression, but several studies have since evaluated its benefit in fibromyalgia A meta-analysis of six randomized trials of duloxetine compared with placebo in more than 2,000 patients with fibromyalgia showed a significant improvement in a pain reduction at weeks 12 and 28. Overall, the number needed to treat was eight.

Doses can range from 30 to 120mg daily, however, many patients with fibromyalgia cannot tolerate doses above 60mg. Common side effects include a headache, palpitations, nausea, and flushing. Some patients find that duloxetine causes drowsiness and should take it before bed, while a smaller number of patients find it stimulating, and thus benefit more from taking it in early in the day.

Milnacipran – is another SNRI recommended for the management of fibromyalgia. Trial data suggest that milnacipran improved quality of life and patient reported pain in around 15% of participants above that of placebo. The usual marketed dose of milnacipran is 50mg twice daily. However, many patients only tolerate much smaller doses, such as 25mg once or twice daily. Patients should be initiated on a dose of 25mg daily and then titrated upwards by 25mg daily at a minimum of every few days. Milnacipran has a similar side effect profile to duloxetine but has stronger noradrenergic qualities than duloxetine and for this reason may be more stimulating.

Patients with prominent fatigue symptoms may benefit from SNRIs, in particular, milnacipran, but they may be less appropriate for those patients with significant insomnia. Concurrent depressive or anxiety symptoms may be another reason for the preference of these agents in individual patients.

Duloxetine is metabolized via the cytochrome (CY) P450 2D6 pathway, a system which metabolizes around 25% of clinically used drugs, and there is, therefore, a high risk of drug interactions Variations in the metabolism of duloxetine can occur due to polymorphisms of the 2D6 gene. By comparison, milnacipran is not metabolized via the CYP450 pathway and, as such, drug interactions are much less likely.

SNRIs can be combined with pregabalin and simple analgesics, however, caution should be taken when combining SNRIs with tricyclic antidepressants or tramadol due to the potential risk of serotonin syndrome. Low doses in combination may be considered with careful patient education and monitoring. The symptoms of serotonin syndrome are variable and include cognitive changes such as agitation, autonomic symptoms (e.g. flushing and sweating), and neuromuscular symptoms (e.g. tremor). The exact incidence of serotonin syndrome is unknown due to the lack of large studies and variations in diagnostic criteria, however, potent CYP450 2D6 inhibitors, increased age, and higher doses increase the risk of this complication Most cases are mild and self-limiting on drug cessation, however, rare severe cases can be life-threatening. SNRIs are recommended in both the EULAR and Canadian Guidelines

Selective serotonin reuptake inhibitors (SSRIs)

As discussed above, the modulation of serotonin alone is of less benefit than dual modulation of noradrenaline and serotonin together in the treatment of fibromyalgia. Several studies have evaluated the use of SSRIs in fibromyalgia with inconsistent results. A meta-analysis of seven studies demonstrated some benefit when compared with placebo, although the quality of the study overall was low and the authors reported that there was no unbiased high-quality data to support the use of SSRIs in the management of fibromyalgia The EULAR guidelines recommend against the use of SSRIs, while the Canadian guidelines suggest their use may be appropriate as an alternative to SNRIs. Common side effects associated with SSRIs include nausea, sexual dysfunction, dry mouth, drowsiness, and insomnia.

Gabapentinoids

Pregabalin – was originally marketed as an antiepileptic but is now commonly used for pain management. It mediates its effects by binding to voltage-gated calcium channels, reducing calcium influx at sensitized spinal cord neurons, thereby reducing the release of neuroactive molecules, including glutamate, substance P and noradrenaline, into the synapse. It has been shown that patients with fibromyalgia have increased levels of glutamate in their insula, an area of the brain involved in pain processing and that pregabalin can reduce this, leading to an associated decreased level of perceived pain. Several studies have evaluated its effectiveness in fibromyalgia, and a recent Cochrane Review reported pregabalin reduces pain with tolerable side effects in around 10% of patients above that of placebo.

The full dose of pregabalin given to patients can be as high as 300mg twice daily, but similarly, with many other medications, patients with fibromyalgia are poorly tolerant of such doses. Pregabalin can be initiated at a dose of 25–75mg daily, with the additional 25–75mg every one to two weeks as tolerated. Common side effects associated with pregabalin include dizziness, somnolence, and weight gain. If somnolence is prominent, patients may benefit from taking pregabalin only at night to enhance sleep and minimize daytime drowsiness. Drug interactions are uncommon and pregabalin can be safely added to SNRIs, tricyclic antidepressants (TCAs) and most analgesics. It may be best for patients with prominent pain and sleep disturbance and is less effective for fatigue. Pregabalin is recommended in both the EULAR and Canadian guidelines

Gabapentin – is another antiepileptic medication that is sometimes used to treat fibromyalgia. Gabapentin has a similar mechanism of action to pregabalin and exerts its effects via modulating neuronal voltage-gated calcium channels It has a shorter half-life than pregabalin, and is usually given three or more times daily, which may make dose titration easier, however, this does increase pill burden. Gabapentin is cheaper than pregabalin and may be prescribed for this reason. A small randomized trial of 150 patients reported that patients taking 1200-2400mg of gabapentin were more likely to have a 30% reduction in their pain at week 12, with a response rate around 20% higher in the treatment group compared with placebo , However, a recent Cochrane Review concluded that there is currently insufficient evidence to recommend gabapentin for routine use in fibromyalgia treatment The EULAR guidelines make no recommendation for or against gabapentin given limited data; however, the Canadian guidelines do not differentiate between pregabalin and gabapentin.

Tricyclic antidepressants (TCAs)

Like SNRIs, TCAs mediate their effects via modulation of noradrenaline and serotonin and were originally developed for the treatment of depression.

Amitriptyline is a TCA commonly prescribed for the management of fibromyalgia and short-term studies have shown clinical improvements in 15-20% of patients taking amitriptyline above that of placebo. Nortriptyline is an alternative option; however, fewer studies have examined the use of this agent.

Side effects from amitriptyline are common and include dry mouth, constipation, daytime drowsiness, and mental clouding. Like pregabalin, patients may benefit from taking this medication in the evening to promote sleep and minimize daytime side effects. Typically, much smaller doses are used in fibromyalgia than in depression, with between 10mg and 25mg usually prescribed as an early evening dose, with doses above 50mg seldom being used for this indication. It can be co-prescribed with pregabalin, SSRIs and simple analgesics, and cautiously with SNRI medications as discussed above. It may be particularly helpful in patients in whom insomnia is a prominent clinical feature.

Cyclobenzaprine – is a medication with a similar tricyclic structure to amitriptyline, but is not known to have antidepressant effects. It is available in the United States but not in the UK. A meta-analysis of the use of this medication in patients with fibromyalgia reported that it leads to symptomatic improvement in one in five patients. The side effects commonly associated with the use of cyclobenzaprine are similar to amitriptyline. Doses of 1–4mg at night has been shown to improve sleep. Both amitriptyline and cyclobenzaprine are recommended in the EULAR and Canadian guidelines.

Tramadol

Tramadol is a weak opioid with mild serotonin-noradrenaline reuptake inhibition. A small study showed the benefit of tramadol in combination with paracetamol in patients with fibromyalgia compared with placebo. In this study, patients were given 37.5mg of tramadol four times per day. While difficult to confirm, it is likely that the positive effects of tramadol in fibromyalgia are due to their SNRI activity as opposed to their opioid effect. As discussed in the next section, opioids are unlikely to be beneficial in fibromyalgia, with side effects likely to include drowsiness, dizziness, and nausea. Tramadol is recommended in the EULAR fibromyalgia guidelines, however, in the Canadian guidelines, it is suggested that tramadol is reserved for those patients with significant symptoms not responding to the above-mentioned drug classes. It should be used with caution with SSRIs, SNRIs, and TCAs and, as it is metabolized by CYP450 2D6 and 3A4 pathways, medications that are potent inhibitors of this pathway, such as paroxetine or fluoxetine, should be avoided.

Contraindications, warning and precautions with regards to the most commonly used drugs in fibromyalgia syndrome (FMS) as per summary of product characteristic (SPC).

DrugContraindicationsWarning and PrecautionsLast Update
AmitriptylinePrior Hypersensitivity
Concomitant use of MAOI
Acute recovery phase following myocardial infarction
Mania
Sever liver disease
Congestive heart failure
Suicidality
Hyponatraemia
QT interval prolongation on ECG
Blood dyscrasias
5 December 2016
DuloxetineSerotonin syndrome and MAOIs.
Concomitant use of irreversible MOAi, fluvoxamine, ciprofloxacin or enoxacin
Liver disease resulting in hepatic impairment
Severe renal impairment
Mania and seizures
Mydriasis
Hypertension
Renal impairment
Serotonin syndrome
Suicide
Diabetic peripheral neuropathic pain
Hyponatraemia
8 February 2008
PregabalinKnown hypersensitivity to pregabalin (PGB) or any of its components-Hypersensitivity reaction
-Dizziness, somnolence, loss of consciousness
-Vision-related effects
-Increase risk of suicidal thoughts and behaviours
-Encephalopathy
Reduced lower gastrointestinal tract function
14 November 2016
Tramadol HydrochlorideHypersensitivity to tramadol or other opioids
Severe hepatic/renal impairment
MOA or within 2 weeks of their withdrawal
Withdrawal symptoms
Dependence and abuse
Convulsive disorders
22 September 2015
MilnacipranHypersensitivityConcomitant use to MAOI
Liver disease resulting in hepatic impairment
Uncontrolled hypertensionSevere renal impairment
As per Duloxetine8 February 2017
SSRI (Fluoxetine)Concomitant of metoprolol and irreversible non-selective MAO, hypersensitivity to the active substanceSuicidality
Rash and allergic reaction
Seizures
Mania
Hepatic/renal function
Prolonged QT
22 December 2016

Abbreviation: MAOi = monoamine oxidase inhibitor, SSRI = selective serotonin reuptake inhibitor.

Combination medications

It should be noted that in many of the discussed trials, medications were administered as a single agent in the absence of concurrent non-pharmacological management strategies, which is not consistent with the typical way these medications are used in clinical practice. Although there are limited data to support this approach, many patients who do not respond to a single agent receive combination therapy. A retrospective study reported that patients receiving either milnacipran or duloxetine in conjunction with pregabalin had improved pain scores compared with any of the three agents alone A further study suggested that adding milnacipran to pregabalin resulted in higher response rates than pregabalin alone. However, not unexpectedly, there were also more side effects associated with dual therapy. Further studies are required to investigate the efficacy of combination therapy and drug interactions need careful consideration.

Medications not recommended for treatment of fibromyalgia. Where no recommendation for/against is offered, a grey box is used. LE: level of evidence.

DrugAWMF (LE)EULARCanadian Guideline
AcetaminophenNo positive or negative recommendationMay be used in some patients (level 5)
Antiviral DrugsStrong negative (2b)
AnxiolyticsStrong negative (2b)
Dopamine agonistsStrong negative (2)a
FlupirtineNegative (4)
Hormones (Growth hormone, Glucocorticoids, Calcitonin, oestrogen)Strong negative (3a)Strong against
HypnoticsStrong negative (3a)
InterferonStrong negative (3a)
KetamineStrong negative (4a)
Local anaestheticStrong negative (3a)
Monoamine oxidase inhibitorNegative (2a)Weak against
Sodium OxybateStrong negative (3a)Strong against
NeurolepticsStrong negative (3a)
Strong opioidsStrong negative (4b)Strong against (5)Discouraged Level 5, grade D
Serotonin Receptor AntagonistStrong negative (3a)

Anti-inflammatory medications

Nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids act peripherally to reduce inflammation at the site of tissue damage. Given that the pain experienced by patients with fibromyalgia is not nociceptive, it is not surprising that these medications are not of particular benefit. Small studies have evaluated the use of both NSAIDs and low-to-moderate dose glucocorticoids in fibromyalgia and have found no benefit over placebo. Any concurrent inflammatory or mechanical musculoskeletal condition should be treated appropriately, which may include the use of these medications in some patients.

Opioids

Despite their common use, there is no evidence to suggest opioid medication is beneficial in fibromyalgia and, to the contrary, these medications may be associated with significant harm. There are no randomized trials available; however, longitudinal observational studies have suggested that patients with fibromyalgia taking opioid medications have worse outcomes than those patients not taking opioids in terms of pain, function, and quality of life.

There is evidence to suggest that patients with fibromyalgia have abnormal endogenous opioidergic activity. Patients with fibromyalgia have been shown to have reduced μ-opioid receptor binding in several central nervous systems (CNS) centers that are involved in processing pain, including the amygdala, cingulate and nucleus accumbens This reduced binding potential is associated with increased perceived pain. Furthermore, endogenous opioids have been shown to be elevated in the CSF of fibromyalgia patients. Together, these findings may be suggestive of a chronically activated endogenous opioid system leading to downregulation of opioid receptors. This explanation provides a rationale for why fibromyalgia patients respond poorly to opioid medication. In line with this, it has been shown that patients with more fibromyalgia symptoms were likely to require significantly more opioid post joint replacement surgery than those patients with fewer fibromyalgia symptoms.

Beyond this, common opioid-related side effects such as drowsiness and mental clouding are likely to exacerbate symptoms of fibromyalgia. Enteral side effects of opioids may worsen irritable bowel syndrome which is commonly associated with fibromyalgia. A further concern is that of opioid hyperalgesia, which can occur with prolonged opioid use and causes a paradoxical increase in pain sensitivity. This phenomenon may be related to sensitization of pro-nociceptive pathways secondary to opioid induced toll like receptor 4 (TLR4) activation in glial cells. TLR4 activation leads to the release of neuroexcitatory and proinflammatory products. Opioids, excluding tramadol, are not recommended by any current guidelines for the management of fibromyalgia.

Medications requiring more study to assess efficacy in fibromyalgia

Low dose naltrexone

Interestingly, small studies have evaluated the use of low dose naltrexone, an opioid antagonist, in fibromyalgia on the basis that fibromyalgia patients may have a chronically activated endogenous opioid system. It is likely that low doses of naltrexone exert an analgesic effect via antagonism of TLR4 as opposed to the opioid receptor antagonism seen at higher doses. Small studies have suggested efficacy, reporting 20–30% of patients achieving a significant pain reduction above placebo. Larger studies are required before recommendations can be made in regard to the routine use of naltrexone in the management of fibromyalgia.

NMDAR inhibitors

The N-methyl-D-aspartate receptor (NMDAR) is involved in the spinal cord and brain sensory pathway neural transmission via interaction with the neurotransmitter glutamate. As previously discussed, fibromyalgia patients have been shown to have elevated levels of glutamate in their central nervous system and CSF.

Several small studies have evaluated intravenous low dose ketamine, a non-competitive NMDAR antagonist, in patients with fibromyalgia, with around half of patients experiencing a reduction in pain intensity of more than 50%. However, duration of follow up was brief and there are no long-term data for this medication.

Memantine, another noncompetitive NMDAR inhibitor, was evaluated in a small randomized trial in fibromyalgia and was found to be more successful than placebo at reducing pain intensity by 50%, with a number needed to treat of six. Further studies of NMDAR inhibitors in fibromyalgia are required before recommendations can be made.

Dopamine agonists

Dopamine is a neurotransmitter with multiple functions, including a central role in the modulation of pain via descending inhibitory pathways. Using functional imaging, it was shown that fibromyalgia patients have abnormal dopaminergic activity, with reduced CNS release of dopamine in response to painful stimuli In a small trial, 42% of patients with fibromyalgia receiving pramipexole, a dopamine agonist, reported a 50% improvement in pain compared with 14% in placebo. However, terguride, a partial dopamine agonist, did not show any benefit. Pramipexole may also be helpful for patients with symptomatic restless leg syndrome, which is a common comorbidity with fibromyalgia. Further studies are required.

Cannabinoids

Cannabinoids are discussed as an option for management in the Canadian treatment guidelines. A recent Cochrane Review evaluated the use of cannabinoid medication in the treatment of fibromyalgia. Two studies of nabilone, a synthetic cannabinoid, were examined. Both were of very low quality and the authors concluded that there is currently no quality evidence to suggest that cannabinoids are effective for fibromyalgia symptoms.

Other experimental agents

Stress Management –  Many patients with fibromyalgia have increased levels of stress and feelings of depression, anxiety, and frustration. Several treatment options are available such as cognitive behavioral therapy; including relaxation training, group therapy, and biofeedback, which are some of the useful options.

Alternative Therapies – Chinese herbal medications, Chinese herbal tea, acupuncture, Tai-chi are the different modalities available but more research is required in these fields. It has also been suggested that acupuncture triggers the release of endorphins into the blood stream and are body’s natural pain relievers.

Flupirtine is a centrally acting agent that is thought to indirectly inhibit the NMDAR by activation of the G-protein regulated inwardly rectifying potassium (GIRK) ion channel. There is evidence to suggest efficacy in acute pain, with some efficacy in fibromyalgia reported in a small case series. Melatonin, an agent typically used for sleep disturbance, has also been shown to have analgesic properties, the mechanisms of which remain incompletely understood. In several small randomized trials, melatonin was shown to be superior to placebo when used either alone or in combination with other agents in treating fibromyalgia pain and sleep disturbance.

Exercise – Exercise is highly recommended even though people with fibromyalgia may be reluctant to exercise because of their pain.  Exercise is important to prevent the muscles from losing strength due to lack of use.  Other benefits of regular exercise include sleep promotion, aiding digestion, increasing blood flow and improving muscle tone.  It is best to start with small amounts of low impact exercise (such as walking) on a daily basis, and gradually increase this as tolerated. Physical activity can be taken in many ways, including activities such as walking, jogging or sports. Exercise is a way of responding to stress which allows the discharge of the energy the body is anticipating.

Physical and occupational therapy may help to reduce the effects of fibromyalgia on everyday life.  A physical therapist can teach exercises that will improve strength, flexibility, and stamina.  An occupational therapist can help make adjustments to workstations or the way that certain tasks are performed to reduce the level of stress on the body.

Rest and sleep – Rest is also important in managing fibromyalgia.  People with fibromyalgia often feel exhausted after only small amounts of activity.  It is often helpful, therefore, to rest regularly during the day and even during activity if it is needed.  Even 5-10 minute periods of rest can be helpful.   Sleep is often inadequate in quality for people with fibromyalgia.  It is not advisable to use sleeping tablets unless they are absolutely necessary, and then only for brief periods of time.  Some methods that may help to gain more restful sleep include avoiding alcohol and coffee in the evening, using the bedroom only for sleep (ie: not for working or eating), ensuring the room is dark when trying to sleep and having a regular time for going to bed.

Stress reduction and relaxation – Stress reduction is important as increased stress can worsen fibromyalgia symptoms.   Finding methods of relaxation (such as reading or listening to music) that suit the individual with fibromyalgia can be helpful in stress reduction.  Talking about the condition with friends and family can also be helpful. Some people may find it helpful to work with a professional counselor or psychologist to develop relaxation techniques and strategies to cope with the pain. A psychological technique known as Cognitive Behavioural Therapy (CBT) has been shown to help people with fibromyalgia.

Alternative therapy

Alternative therapies such as acupuncture/acupressure, homeopathy, hot and cold packs, massage therapy, yoga and tai chi, nutritional supplements and dietary modifications, herbal.

Cognitive behavioral therapy

Non-pharmacological components include cognitive-behavioral therapy (CBT), exercise and psychoeducation (specifically, sleep hygiene). CBT and related psychological and behavioral therapies have a small to moderate effect in reducing symptoms of fibromyalgia. Effect sizes tend to be small when CBT is used as a stand-alone treatment for FM patients, but these improve significantly when CBT is part of a wider multidisciplinary treatment program. The greatest benefit occurs when CBT is used along with exercise.

A 2010 systematic review of 14 studies reported that CBT improves self-efficacy or coping with pain and reduces the number of physician visits at post-treatment, but has no significant effect on pain, fatigue, sleep or health-related quality of life at post-treatment or follow-up. Depressed mood was also improved but this could not be distinguished from some risks of bias.

Mind-body therapy

Mind-body therapies focus on interactions among the brain, mind, body, and behavior. The National Centre for Complementary and Alternative Medicine defines the treatments under the holistic principle that mind-body are interconnected and through treatment, there is an improvement in psychological and physical well-being, and allow patients to have an active role in their treatment. There are several therapies such as mindfulness, movement therapy (yoga, tai chi), psychological (including CBT) and biofeedback (use of technology to give audio/visual feedback on physiological processes like heart rate). There is only weak evidence that psychological intervention is effective in the treatment of fibromyalgia and no good evidence for the benefit of other mind-body therapies

References

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