Fibromyalgia Study Guide

• Study notes on Fibromyalgia by Dr Caglayan Aslanbas.

Definition of Fibromyalgia

• Fibromyalgia was described in the nineteenth century.
• Fibrositis was coined the term in 1904 by Gowers.
• Graham in 1950 introduced the modern concept of fibromyalgia as a pain syndrome in the absence of a specific organic disease.
• In the mid-1970s Smythe and Moldofsky coined the term fibromyalgia defining regions of extreme tenderness or "tender points".
• In 1990 the American College of Rheumatology committee wrote the widely used diagnostic criteria.
• ACR diagnostic criteria for fibromyalgia was recently modified in 2010.
• Fibromyalgia is characterized by chronic widespread pain at multiple tender points and joint stiffness.
• Further systemic symptoms include; mood disorders, fatigue, cognitive dysfunction, and insomnia.
• Pain must last for at least 3 months to be considered a symptom.
• There must be no well-defined underlying organic disease.
• Widespread pain indicators are pain in both sides of the body, both above and below the waistline and axial skeletal pain.
• The above symptoms must occur with tenderness in at least 11 of 18 specific tender points.

Onset and Risk Factors

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

Etiology and Pathogenesis of Fibromyalgia

• Etiology and pathogenesis are still not fully understood.
• Several factors such as dysfunction of the central and autonomic nervous systems are seem to be involved.
• Also, neurotransmitters, hormones and the immune system.
• External stressors and psychiatric aspects.

CNS Involvement

• Central sensitization is considered the main mechanism involved.
• Central sensitization is defined by an increased response to stimulation mediated by CNS signaling.
• Central sensitization is the consequence of spontaneous nerve activity, enlarged receptive fields, and augmented stimulus responses transmitted by primary afferent fibers.
• The "windup” phenomenon reflects the increased excitability of spinal cord neurons.
• After a painful stimulus, subsequent stimuli of the same intensity are perceived as stronger.
• Windup "occurs normally in everyone but is excessive in fibromyalgic patients."
• Fibromyalgia can cause abnormalities in pain processing by the central nervous system (CNS).
• It can cause alteration of pain perception.

Neuroendocrine And Autonomic Nervous System Involvement

• Fibromyalgia is considered a stress-related disorder involving the hypothalamic-pituitary-adrenal (HPA) axis.
• Studies show elevated cortisol levels, particularly in the evening, with a disrupted circadian rhythm.
• Patients show high values of adrenocorticotropic hormone (ACTH) basally.
• Chronic hyposecretion of corticotropin-releasing hormone (CRH)
• Alterations probably related to low levels of 5-HT are observed because serotoninergic fibers regulate the HPA axis function.
• GH is mainly secreted during stage 4 of sleep, which is disrupted in fibromyalgia patients.
• Second, these patients have high levels of somatostatin or a GH inhibitor.
• Sympathetic nervous system is persistently hyperactive, but hyporeactive to stress.
• High serum levels of neuropeptide Y which is normally secreted with norepinephrine, are supposed to be a sign of this dysautonomic state.

Sleep Disturbances

• Patients often complain of sleep disorders and these are probably involved in its pathogenesis
• The fourth phase of sleep is the most disturbed leading to a deficit of GH and insulin-like growth factor 1 (IGF-1)
• A deficit of these hormones involved in muscle microtrauma repair could affect the tissue healing.

Genetic Factors

• Genetic predisposition is likely to be an important factor suggested by several familial studies.
• Transmission is thought to be polygenic.
• Among the various genes investigated, the most important are associated with neurotransmitters.
• The Serotonin transporter gene with S (short) allele is more frequent.
• It is more frequent in patients affected by fibromyalgia and by psychological distress.
• Other genes presumed to be involved are the catechol-O-methyltransferase gene and the dopamine D4 receptor gene and the HLA-region

Immune System

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

Psychiatric Aspects

• Psychiatric problems seem to contribute considerably to the fibromyalgia development.
• The prevalence of psychiatric conditions is higher than among rheumatic diseases.
• Common disorders associated are anxiety, somatization, dysthymia, panic disorders, posttraumatic stress, and overall depression.
• Depression is more frequently associated with fibromyalgia
• Dysfunction of the 5-HT system might play a role.
• Depression worsens fibromyalgic symptoms and vice versa, and antidepressants represent a cornerstone of fibromyalgia therapy.

Peripheral Tissues

• Peripheral tissues such as skin, muscles, and microvessels are coming under investigation.
• Vascular dysregulation in muscles is an inadequate response to oxidative stress exacerbated by the nocturnal fall in saturation.
• Increased IL-1 in cutaneous tissues occurs.
• Increased substance P in muscles.
• DNA fragmentations of muscle fibers, all could potentially be involved in the condition.

Trigger Factors

• Infections seem to be able to induce fibromyalgia even if a direct causal relationship is not documented.
• Viruses like HIV, Coxsackie B, and Parvovirus plus bacteria like Borrelia could be involved.
• Trigger factors may include cytokines and glial cells by Bacteria.
• Physical trauma, vaccinations, and chemical substances

Etiology

• Some experts believe that fibromyalgia 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 of fibromyalgia is not known
• No gene, receptor, specific neurotransmitter, or tissue alteration has been associated withFibromyalgia.
• There is no specific laboratory test or imaging method for diagnosis.

Diagnosis

• Diagnosis is difficult and frequently missed because symptoms are vague and generalized
• Main symptoms include pain, fatigue, and sleep disturbance
• Pain typically is diffuse, multifocal, deep, gnawing, or burning.
• It often waxes and wanes and is frequently migratory
• Must rule out additional symptoms: weight fluctuations, morning stiffness, irritable bowel disease and bladder syndrome, cognitive disturbance, headaches, restless legs, heat, cold intolerance and Raynaud's phenomenon.
• Musculoskeletal and neurological examinations are normal in fibromyalgia patients.
• A detectable sign is the presence of tender points, as explained by the American College of Rheumatology (ACR)
• Specific places on the body are painful when a standard amount of pressure (about 4kg) is applied.
• Diagnosis is principally based on the two major diagnostic criteria defined by the ACR in 1990.
• (1) a history of widespread musculoskeletal pain present for at least three months.
• (2) tenderness in at least 11 of 18 defined tender points.
• (both criteria must be satisfied)
• The pain must affect both sides of the body, must affect areas above and below the waist, and must be also axial.
• A tender point must be evaluated by digital palpation with about 4kg of pressure (thumb nail bed blanches)
• The subject must state that the palpation was “painful” (“irritating” is not sufficient)
• 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.
• Bilateral Fibromyalgia Tender Points affect low cervical region, costochondral junctions, Occiput and trapezius muscles
• Lateral epicondyle and Gluteal and Supraspinatus muscles show pain.
• In addition, testing the Greater trochanter and Knee for tenderness.

Treatment

• Goals of treatment include alleviate pain, increase restorative sleep, and improve physical function through a reduction in associated symptoms
• A multifaceted treatment approach involving nonpharmacological strategies and medication is required.
• medications such as NSAIDs like ibuprofen and naproxen are no better than placebo.
• The prevalence of opioid use is unknown.
• Opioids are not recommended by current management guidelines.
• Tramadol, an atypical pain reliever has been found beneficial.
• Tramadol changes the CNS (the reuptake of serotonin and norepinephrine) and, used with acetaminophen helps with pain.
• Tramadol has theoretical risks of seizures and serotoninergic syndrome if combined with selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenalin reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and triptans
• Antidepressants and neuromodulating antiepileptics substantially reduce fibromyalgia symptoms.
• Serotonin and norepinephrine reuptake inhibitors have been found to provide the best result.
• The class includes dualoxetine and milnacipran, that both reduce activity of noradrenergic antinociceptive pathways.
• Duloxetine should be considered in patients with significant depression symptoms; maximum dosage is 60 mg daily, but, start at 30 mg daily to reduce nausea
• Milnacipran with norepinephrine specificity can help with fatigue or cognitive dysfunction.
• The initial dose of 12.5mg is increased over several weeks up to 100mg, given in two separate doses.
• Pregabalin that is analgesic, anxiolytic-like, and anticonvulsant in animal models binds to the primary binding site a2-6.
• Pregabalin reduces calcium influx at nerve terminals, reducing the release of neurochemicals.
• Reducing neurotransmitter release from neurons in the spinal cord and brain may be clinically beneficial.
• Pregabalin has side effects: weight gain, dizziness, somnolence, and peripheral edema.
• It can cause angioedema with angiotensin-converting-enzyme (ACE) inhibitors.
• The recommended dose is 300–450 mg daily with some patients respond to lower doses.
• Start with a single low dose (50-75 mg) at bedtime.
• Mechanisms of action of pregabalin, duloxetine, and milnacipran are thought to be related to proposed pathophysiologies of fibromyalgia.
• However, these therapeutic agents are still not effective for all fibromyalgia patients
• Tricyclic antidepressants (TCAs) are effective over the short term, specifically amitriptyline and cyclobenzaprine.
• By inhibiting the reuptake of both serotonin and norepinephrine, tricyclic compounds enhance both secretions.
• This results in a reduction in pain.
• Nonpharmacologic treatments most consistently linked to fibromyalgia improvements are aerobic exercise and strength training.
• Effective aerobic exercise focuses on stretching with gradual progression to strengthening and reconditioning exercise.
• Aquatic exercises and balneotherapy are interventions.
• Psychological pain management skills have reported benefits.
• Additional options are: Acupuncture, Hypnotherapy and Physical therapy.