Fibromyalgia: Definition and History

Fibromyalgia Definition

• Fibromyalgia was described in the nineteenth century
• In 1904, Gowers used the term “fibrositis"
• Graham introduced the modern concept of fibromyalgia as “pain syndrome” in 1950, in the absence of a specific organic disease
• Smythe and Moldofsky coined the term “fibromyalgia” in the mid-1970s and identified regions of extreme tenderness called “tender points.”
• The American College of Rheumatology committee wrote the widely used diagnostic criteria in 1990
• ACR diagnostic criteria for fibromyalgia have recently been modified (2010)
• Fibromyalgia is characterized by chronic widespread pain at multiple tender points, joint stiffness, and systemic symptoms like mood disorders, fatigue, cognitive dysfunction, and insomnia
• Widespread pain lasting for at least 3 months is a symptom
• It is a condition without a well-defined underlying organic disease
• Pain is qualified as widespread when present on both sides of the body, above and below the waistline, and as axial skeletal pain
• Diagnosed in combination with tenderness at 11+ of 18 specific tender points

Fibromyalgia Commonality

• The onset typically occurs between ages 25 and 40
• It is predominant in women, with a 10:1 female-to-male ratio
• Genetic predisposition may play a role
• First-degree relatives of patients with fibromyalgia have an eight-fold greater risk compared to the general population
• Patients have a two- to seven-fold increased risk of depression, anxiety, headache, irritable bowel syndrome, systemic lupus erythematosus, and rheumatoid arthritis compared to healthy individuals

Etiology and Pathogenesis of Fibromyalgia

• The etiology is not fully understood
• Several factors, such as dysfunction of the central and autonomic nervous systems, neurotransmitters, hormones, the immune system, external stressors, and psychiatric aspects seem to be involved
• Central sensitization is considered the main mechanism involves
• Increasing the response to stimulation mediated by CNS signaling defines it
• Central sensitization results from spontaneous nerve activity, enlarged receptive fields, and augmented stimulus responses transmitted by primary afferent fibers
• The "windup" phenomenon reflects increased excitability of spinal cord neurons; after a painful stimulus, subsequent stimuli of the same intensity are perceived as stronger
• The "windup” occurs normally in everyone, but it is excessive in fibromyalgia patients
• There are abnormalities in pain processing by the central nervous system (CNS)
• There is an alteration of pain perception

Other Systems Affected by Fibromyalgia

• It is considered a stress-related disorder, which means the hypothalamic-pituitary-adrenal (HPA) axis is involved
• Elevated cortisol levels are shown in studies, particularly in the evening, associated with a disrupted circadian rhythm
• Higher adrenocorticotropic hormone (ACTH) values are found in these patients
• Chronic hyposecretion of corticotropin-releasing hormone (CRH)
• Alterations are related to low levels of 5-HT because serotoninergic fibers regulate the HPA axis function
• GH is mainly secreted during stage 4 of sleep, but this phase is disrupted in patients.
• High levels of somatostatin, a GH inhibitor, are found in these patients
• Sympathetic nervous system is persistently hyperactive, but hyporeactive to stress
• High serum levels of neuropeptide Y are usually secreted along with norepinephrine and show dysautonomia

Fibromyalgia Cause

• Sleep disorders are often reported and play a role in pathogenesis
• The fourth phase of sleep is the most disturbed
• A direct consequence of disturbed sleep should be a deficit of GH and insulin-like growth factor 1 (IGF-1)
• Muscle microtrauma repair is affected by these hormones, and so healing of this tissue could be affected

The Genetic Factors of Fibromyalgia

• Genetic predisposition seems an important factor from familial studies
• Transmission is polygenic
• The most important genes investigated are associated with neurotransmitters
• The serotonin transporter gene is characterized by a single nucleotide polymorphism; the “S” (short) allele is more frequent in patients and psychological distress
• Other genes are the catechol-O-methyltransferase gene, the dopamine D4 receptor gene , and the HLA-region

The Effect of The Immune System On Fibromyalgia

• Fibromyalgia is common in patients with autoimmune disease
• Different studies in the literature deal with autoantibodies in fibromyalgia with equivocal results
• Several authors investigated the association between this disease and antipolymer antibodies (APAs)
• The results are controversial and APAs cannot be used as a diagnostic marker

Psychiatric Issues Related To Fibromyalgia

• Psychiatric problems contribute to the development
• Fibromyalgia patients have a higher prevalence of psychiatric conditions compared to those with other rheumatic diseases
• Common disorders are anxiety, somatization, dysthymia, panic disorders, posttraumatic stress, and overall depression
• Depression is more frequently associated
• Dysfunction of the 5-HT system plays a role
• Depression can worsen fibromyalgic symptoms
• Antidepressants are a cornerstone of therapy

Peripheral Tissues Related to Fibromyalgia

• Peripheral tissues such as skin, muscles, and microvessels are under closer investigation
• Vascular dysregulation in muscles exhibits an inadequate response to oxidative stress exacerbated by the nocturnal fall in saturation
• Increased IL-1 is found in cutaneous tissues
• Increased substance P is found in muscles
• DNA fragmentation of muscle fibers may play a role

Trigger Factors of Fibromyalgia

• Infections may induce fibromyalgia even if a direct causal relationship is undocumented
• Viruses like HCV, HIV, Coxsackie B, and Parvovirus and bacteria like Borrelia could be involved
• Cytokines and glial cells may also play a role
• Physical trauma ,vaccinations , and chemical substances may also be trigger factors

Etiology of Fibromyalgia

• Some experts suggest it is a central sensitivity syndrome with abnormalities in pain processing by the central nervous system (CNS)
• Some studies have indicated an alteration of pain perception
• The cause is unknown
• No gene, receptor, specific neurotransmitter, or alteration of tissue has been found
• There is no specific laboratory test or imaging method for diagnosis

Diagnosis of Fibromyalgia

• Diagnosing fibromyalgia is hard because symptoms are vague and generalized
• Three main symptoms are referred to by almost every patient: pain, fatigue, and sleep disturbance
• A physician must investigate the features of the pain
• The pain is typically diffuse, multifocal, deep, gnawing, or burning,
• It often waxes and wanes and is frequently migratory

Other Considerations for Diagnosis

• It is important to evaluate additional symptoms, such as weight fluctuations, morning stiffness, irritable bowel disease, cognitive disturbance, headaches, heat and cold intolerance, irritable bladder syndrome, restless legs, and Raynaud's phenomenon
• Musculoskeletal and neurological examinations are normal
• Tender points explained by the ACR are a detectable sign
• They are specific places on the body that are painful when applying pressure of about 4 kg

How To Diagnose Fibromylagia

• Diagnosis is based on the two major diagnostic criteria defined by the ACR in 1990
• A history of widespread musculoskeletal pain must be present for at least 3 months
• Tenderness in at least 11 of 18 defined tender points
• Both criteria must be satisfied
• The pain must affect both sides of the body, above and below the waist, and be axial
• For a tender point to be considered positive, evaluate by digital palpation with about 4 kg of pressure (when the thumbnail bed blanches) and the subject must state that palpation was "painful”

What Happens When You Test For Pain?

• The pain should affect at least three of the body’s four quadrants
• There should be no joint swelling
• When testing the tender points with your thumb, apply enough pressure to dent the patient’s skin and turn the tip of your fingernail white
• Patients report pain at the following sites, but controls do not

Bilateral Fibromyalgia Tender Points

• Low cervical region; anterior neck near the transverse process of C5 to C7
• Second rib, costochondral junctions
• Occiput: Insertion of the suboccipital junctions
• Trapezius muscles: Midpoint of the upper border
• Supraspinatus muscles: Medial border of the scapular spine
• Lateral epicondyle: 2 m distal
• Gluteal muscle: Upper outer quadrant
• Greater trochanter: Posterior to the trochanteric process
• Knee: Medial fat pad

Treatment Options

• Treatment goals are to alleviate pain, increase restorative sleep, and improve physical function through reduced symptoms
• A multifaceted treatment approach is required because pain, depression, and other symptoms are linked to inherited and environmental causes
• Multifaceted treatments include both nonpharmacological pain management strategies and medication

Medications for Fibromyalgia Treatment

• Nonsteroidal anti-inflammatory drugs (NSAIDs, like ibuprofen and naproxen), have been shown to be no better than placebo
• The prevalence of opioid use by fibromyalgia patients is unknown
• Opioids are unrecommended by current guidelines for the management of fibromyalgia
• Tramadol is beneficial because it is an atypical pain reliever with a different action on the CNS (reuptake of serotonin and norepinephrine) than narcotics
• When alone or in combination with acetaminophen, it is commonly prescribed at 200–300 mg/day
• There is a theoretical risk of seizures and serotoninergic syndrome combined with selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and triptans
• Both antidepressants and neuromodulating antiepileptics reduce symptoms
• Serotonin and norepinephrine reuptake inhibitors provide the best efficacy and tolerability
• Duloxetine and milnacipran belong to the serotonin-norepinephrine reuptake inhibitor class and reduce pain by increasing the activity of noradrenergic antinociceptive pathways
• Both have shown efficacy in randomized, blinded, controlled studies
• Duloxetine should be considered in patients with significant depression symptoms
• The maximum dosage for treatment is 60 mg daily, but, due to nausea, 30 mg daily is often started
• Milnacipran has increased selectivity for norepinephrine than for serotonin
• It may be helpful in patients with significant fatigue or cognitive dysfunction
• The initial dose is 12.5 mg daily that increases to a maximum daily dose of 100 mg, given in two separate doses

Other Medications

• Pregabalin is an α2-δ ligand with analgesic, anxiolytic-like, and anticonvulsant activity in animal models
• Biochemical studies have found the primary binding site for pregabalin and related gabapentin are α2-δ (type 1)
• α2-δ is an auxiliary protein associated with voltage-gated calcium channels
• The potent binding of pregabalin at the α2-δ site reduces calcium influx at nerve terminals, reducing the release of neurochemicals, including glutamate, noradrenaline, and substance P
• Reducing neurotransmitter release from neurons in the spinal cord and brain may be clinically beneficial
• Pregabalin has significant side effects, including weight gain, dizziness, somnolence, and peripheral edema
• When taken with angiotensin-converting-enzyme (ACE) inhibitors it may cause angioedema
• The recommended dose is 300–450 mg daily, but many patients respond to lower doses
• A single low dose (50–75 mg) at bedtime is frequently employed initially
• The mechanisms of action of pregabalin, duloxetine, and milnacipran are related to proposed pathophysiologies; however, these agents are not effective for all patients
• Tricyclic antidepressants (TCAs) are effective over the short term, which includes the TCA amitriptyline and the biologically similar cyclobenzaprine
• By inhibiting the reuptake of both serotonin and norepinephrine, tricyclic compounds enhance norepinephrine and serotonin neurotransmission, reducing pain

Nonpharmacologic Treatments

• Aerobic exercise and strength training show improvements with fibromyalgia
• Effective exercise focuses on stretching, with gradual progression to strengthening and reconditioning exercise
• Aquatic exercises and balneotherapy are effective
• Psychological pain management skills are efficacious
• Consider acupuncture, hypnotherapy, and physical therapy