Fibromyalgia --- from pathophysiology to evidence-based treatment 財團法人為恭紀念醫院...

Fibromyalgia---from pathophysiology to evidence-based treatment

財團法人為恭紀念醫院 精神科鄧方怡醫師

Conceptual evolution

The misnomer of “fibrositis”

Clinical descriptions of fibromyalgia have been reported since mid-1800s

In 1904, Sir William Gowers introduced the term "Fibrositis" to describe the inflammation of fibrous tissue in his description of low back pain.

Also In 1904, Ralph Stockman first reported evidence of inflammatory changes in the fibrous, intra-muscular septa on biopsies from patients

The misnomer of “fibrositis”

However, subsequent studies of muscle biopsies have failed to reproduce Stockman’s findings.

Various terms, included neurasthenia, fibrositis, fibromyositis, psychogenic, psychosomatic, muscular rheumatism, had been applied in subsequent years.

Yet the term fibrositis has been most resilient and "eventually became synonymous with idiopathic local or diffuse musculoskeletal pain of any type"

Recent development

In the 1970’s, Hench first introduced the term "fibromyalgia".

In the 1980’s, Yunus, proposed the need for a unified classification system as well as the first diagnostic criteria.

Finally, in 1990, the American College of Rheumatology established firm criteria for the classification and diagnosis of fibromyalgia

Diagnostic Labels For Fibromyalgia

Syndrome

DaCosta Syndrome/Shell Shock (brain)Neurasthenia (nerves)Chronic Brucellosis (viral)Failure to Cope (psychological)Fibrositis (muscle inflammation)Affective Spectrum Disorder

(depressive disorder)Fibromyalgia

The ACR criteria

1. History of widespread pain for 3 months in combination with

2. Tenderness at 11 or more of 18 specific tender points sites when digitally palpated with about 4 kg/1.4cm2 per unit area of force

3. No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities

Location of tender points.

* Represents "control" points.

Clinical presentation

What is Fibromyalgia

Pain---Clinical and experimental---Lower pain threshold, allodynia, and hyperalgesia---Involves musculoskeletal structures, skin, and in some

cases, viscera Behavioral disturbances:---Reduced activity, social interaction, function---Avoidance of events that evoke pain---Affective distress

---Increased usage of health services

Neuropsychological symptoms

0102030

405060708090

sleepdisturbance

fatigue anxiety priordepression

SensitivitySpecificity

%

The Criticism of ACR criteria

Many patients with chronic widespread pain may have les than the 11 of 18 tender points

Artificially increase the female predominance

Select for individuals with higher levels of disease-related distress

Fail to capture the “essence”

Epidemiology

Prevalence

10~11% of the population has chronic widespread pain at ay given time

1/5 of above meet the ACR criteria of fibromyalgia

3.4% in women versus 0.5% in men It occurs in 5%~6% of adult patients presenting

at general medical practice and in 10%~20% of adult patients presenting to rheumatologists.

2nd most common disorder observed by rheumatologists

Comorbidity

80%:chronic fatigue syndrome80%:have headaches75%:temporomandibular disorders60%:irritable bowel syndrome

FMS is Multi-system—not just muscles

Chronic Fatigue Syndrome

Non-restorative Sleep

Cognitive Problems (“fibro fog”)

Irritable bowel Irritable bladder Chronic headache

Vulvodynia Orthostatic

Hypotension Postural Orthostatic

Tachycardia (POTS) Anxiety Depression Delayed Post

Exertional Flare-Up

Disability

25.3% of patients received disability payments. However, only 25% of these were specifically for the diagnosis.

31% of patients employed prior to onset of their FM reported loss of employment due to their disease

The disability associated with FM does not change substantially over time according to one 7 year cohort study

Pathophysiology

Aberrant pain processing?

Temporal summation/Wind-up

Pain increases in intensity when painful stimuli are applied repetitively.

Only repetitive stimuli at shorter interval(3 s) resulted in a significant increase in pain ratings.

Central sensitization

Hyperalgesia: augmentation of pain sensation

Allodynia: lowered pain thresholdIt is associated with enlarged

receptive fields and is often occur as a consequence of temporal summation

Greater windup in patients with FM

Prolonged and more intense after-sensations

Evidence from fMRI Patients display a normal “detection”

threshold to sensory stimuli, but exhibit a decreased “noxious threshold”

This phenomenon is independent of psychological factors such as expectancy or hypervigilance

Increased activity of cerebral pain processing areas on fMRI

Evidence from fMRI

Decreased thalamic activity on functional brain scans

fMRI/SPECT studies support the hypothesis that fibromyalgia is characterized by cortical or sub-cortical augmentation of pain processing

Gracely R, et. al. Arthritis Rheum. 2002Gracely R, et. al. Bet Pract res Clin rheum, 2003

Effects of stress

Symptom onset and exacerbation during periods of stress

Clinical response of symptoms to therapeutic agents that alter stress mediators(exercise, TCA, SSRI)

FM has been reported to occur at increased frequency in PTSD patients

Some authors have suggested that it is stress itself that provides the etiology for FM

Disturbance in HPA axis

Healthy HPA axis: circadian variation with high cortisol in AM and low cortisol in PM

FM patients: abnormally elevated plasma cortisol concentration in the evening

It may be related to reduced levels of 5-HT

Disturbance in HPA axis

Marked hypersecretion of ACTH in response to severe acute stressors.

This has been suggested to result from chronic hyposecretion of CRH

HPA abnormalities may be related to depressed autonomic nervous system function.

Common biological pathways shared in FM

and psychiatric disorder

FM patients’ response to dexamethasone suggests similarity with PTSD

Increased “drive” to activity of the HPA axis in melancholic depression

Biochemical abnormalities underlying FM

Levels of 5-HT & primary metabolites of NE and 5-HT are both reduced in patients with FM

Reduced levels of 5-HIAA and tryptophan were associated with increased pain in FM patients

5-HT inhibits the release of neurotransmitters involved in pain processing (substance P, excitatory amino acids)

Biochemical abnormalities underlying FM

Measures of pain intensity in FM patients are positively correlated with the levels of glutamate and aspartate metabolites, glycine, and taurine.

The level of substance P,NGF,glutamate, and aspartate is elevated in CSF of FM patients

Above changes lead to decrease in presynaptic inhibition of pain-related primary afferent neurons

Biochemical abnormalities underlying FM

Low levels of 5-HIAA and high concentrations of substance P were both positively correlated with more severe sleep disturbance

Dysregulation of 5-HT has been associated with depression and anxiety.

Behavior and psychological factors

Psychological distress or psychiatric illness is associated with greater health careseeking behavior at tertiary care facilities

Psychological factors are not necessary or sufficient to produce fibromyalgia.

The most common psychiatric conditions observed in patients with FM include depression (current:30%, life time:60%), dysthymia (10%), panic disorder (7%), and simple phobia (12%)

The Neurobiological / Psychobehavioral Continuum

Neurobiological factors Abnormal sensory

processing Biochemical

dysfunction HPA dysfunction ? Peripheral factors

Psychobehavioral factors General “distress” Cognitive factors Psychiatric

comorbidities Maladaptive illness

behaviors Secondary gain issues

Population Primary Care Tertiary Care Definition factors (e.g., tender points)

Treatment

Pharmacotherapy

Wind-up is dependent on the activation of NMDA receptors by glutamate and substance P

NMDA receptor blockers (ketamine and dextromethorphan) have prove benefit in pain control

NE and 5-HT release from the descending tract and down-regulate dorsal neuron excitability.

Anti-seizure medications are beneficial in inhibiting the release of glutamate and substance P

Medications that block the re-uptake of both NE and 5-HT appear to be more effective than SSRI

Medical strategy

Anti-inflammatory [NSAID, Prednisone]-Failed

Block substance P receptor-Failed Inhibit nerve signal conduction-success Correct insomnia-Success Augment descending inhibition-Success---Increase 5-HT synthesis and /or NE-like---Decrease 5-HT and/or NE reuptake

Treatment of Fibromyalgia SyndromeMedications

Strong Evidence for EfficacyAmitriptyline: often helps sleep and overall well-being; dose, 25-50 mg at bedtime.Cyclobenzaprine: similar response and adverse effects; dose, 10-30 mg at bedtime.

Modest Evidence for EfficacyTramadol: long-term efficacy and tolerability unknown; administered with or without acetaminophen; dose, 200-300 mg/d.Serotonin reuptake inhibitors (SSRIs):Fluoxetine (only one carefully evaluated at this time): dose, 20-80 mg; may be used with tricyclic given at bedtime; uncontrolled report of efficacy using sertraline.

Dual-reuptake inhibitors (SNRIs):Venlafaxine: 1 RCT ineffective but 2 case reports found higher dose effective.Milnacipran: effective in single RCT.Duloxetine: effective in single RCT.

Pregabalin: second-generation anticonvulsant; effective in single RCT.

Weak Evidence for Efficacy Growth hormone: modest improvement in subset of patients with FMS with low growth hormone levels at baseline.5-Hydroxytryptamine (serotonin): methodological problems.Tropisetron: not commercially available.S-adenosyl-methionine: mixed results.

Goldenberg et al. JAMA. 2004

No Evidence for EfficacyOpioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, calcitonin, thyroid hormone, guaifenesin, dehydroepiandrosterone, magnesium.

Nonmedicinal Therapies

Strong Evidence for Efficacy (Wait-List or Flexibility Controls But Not Blinded Trials)Cardiovascular exercise: efficacy not maintained if exercise stops. CBT: improvement often sustained for months.Patient education: group format using lectures, written materials, demonstrations; improvement sustained for 3 to 12 months.Multidisciplinary therapy, such as exercise and CBT or education and exercise.

Moderate Evidence for EfficacyStrength training, acupuncture, hypnotherapy, biofeedback,balneotherapy.

Weak Evidence for EfficacyChiropractic, manual, and massage therapy; electrotherapy, ultrasound.

No Evidence for EfficacyTender (trigger) point injections, flexibility exercise.

Goldenberg et al. JAMA. 2004

Evidence for treatment efficacy was ranked as: Strong: positive results from a meta-analysis or

consistently positive results from more than 1 RCT Moderate:positive results from 1 RCT or largely positive

results from multiple RCTs or consistently positive results from multiple non-RCT studies

Weak:positive results from descriptive and case studies, inconsistent results from RCTs, or both

Goldenberg et al. JAMA. 2004

Stepwise Fibromyalgia Management Step 1 Confirm the diagnosis. Explain the condition. Evaluate and treat comorbid illness, such as mood

disturbances and primary sleep disturbances. Step 2 Trial with low-dose tricyclic antidepressant or

cyclobenzaprine. Begin cardiovascular fitness exercise program. Refer for cognitive behavior therapy or combine that

with exercise.

Step 3 Specialty referral (eg, rheumatologist, physiatrist,

psychiatrist, pain management). Trials with selective serotonin reuptake inhibitor,

serotonin and norepinephrine reuptake inhibitor, or tramadol.

Consider combination medication trial or anticonvulsant.

Thanks for your concentration