Fibromyalgia NOVEL THERAPIES, AND OMT · 2018-10-08 · Complex Etiology: Genetic factors •Strong genetic predisposition d/t marked familial aggregation (11-15) •1st-degree relatives

Fibromyalgia RECENT ADVANCES, NOVEL THERAPIES,

AND OMT

Siddharth S. Arora, DO, MS

Pain Medicine Fellow

Larkin Hospital/Nova Southeastern University

February 23rd, 2017

Pain Management as a Psychiatrist

Conflict of Interest

• None

1

Key Points to Cover

1. Complex etiology involving biological and environmental influences

2. Central Sensitization

3. Pathophysiology supported by imaging studies

4. FM vs SSD and the new DSM-V criteria

5. Traditional treatment and novel therapeutic approaches under investigation

6. OMT and Soft Tissue Techniques

2

Modern Definition

• Chronic, multifaceted, and widespread musculoskeletal pain syndrome involving both central and peripheral sensitization.

• Assoc w/ spectrum of symptoms

• Affects many domains of functioning: somatic and psychological

• Not same as anxiety and MDD (1)

• Billable Codes: • ICD9: 729.1 “Myositis and Myalgia, unspecified”

• ICD10: M79.7 “Fibromyalgia”

3

Early Descriptions

“I, too, have been assigned months of futility, long and weary nights of misery. When I go to bed, I think,`When will it be morning?' But the night drags on, and I toss till dawn...Depression haunts my days. My weary nights are filled with pain as though something were relentlessly gnawing at my bones.”

- Job 7:3-4; 30:16-17 - NLT

4

History

1600s 1816 1824 1904 1972 1975 1976 1981 1987 1990 1990s 2007

5

French physician Guillaume

de Baillou: FM-like

symptoms first given a

name: muscular rheumatism

Dr. Balfour described

tender points

Dr. William Balfour,

surgeon at the Univ of

Edinburgh, gave first full

description of FM

Sir William Gowers

coined the term fibrositis

(= inflammation of

fibers) to denote the

tender points found in

patients with muscular

rheumatism

Dr. Hugh Smythe laid the foundation for the

modern definition of FM by describing

widespread pain and tender points

The first sleep EEG study identifying

the sleep disturbances that

accompany FM was performed

No evidence of inflammation so

changed name from fibrositis to

FM (= pain in muscles and tissues)

The first controlled clinical

study with validation of known

symptoms and tender points was

published

The AMA recognized FM as

a real physical condition

The ACR developed

diagnostic criteria for

FM for research. Later

used in clinical practice

FDA approves first

drug for FM: lyrica

(pregabalin)

Concept of neurohormonal

mechanisms with central

sensitization was

developed

Epidemiology

• Affects 2-8% of US population (2-4)

• Most common cause of widespread MSK pain in women 20-55yo (5)

• Rheum: second to OA as the most common disorder encountered (6)

• Onset: 35-55yo (7)

• Prevalence increases w/age,8 but it can also be seen in children (9-

10)

6

Epidemiology

• Children born prematurely – more likely to show tender points and decr pain threshold vs children delivered term (10) (Buskila, et. al.) • case-control study; 60 pre-term and 60 term

adolescents

• observed in both sexes, but girls had > pain sensitivities than boys

• Higher somatic pain sensitivities higher risk of future pain syndromes?

• more studies needed

7

Epidemiology

• Buskila, et. al hypotheses: • Differences in pain perception d/t:

• lack of myelination of their sensitive fiber

• immature cortical organization of the somatosensory system

• Differences in pain threshold d/t:

• lack of protection of spinal and supraspinal inhibitory pathways

• abnormal behavioral imprinting 2/2 early painful stimuli increased plasticity of neonatal brain future incr vulnerability of CNS to stress and pain d/o

8

Painful stimuli

perceived as

widespread

and durable

Lower pain

threshold

Epidemiology: Painful procedures in the NICU 9

• Diagnostic: • Venipuncture

• Heel lancing

• Lumbar puncture

• ROP examination

• Endoscopy

• Bronchoscopy

• Suprapubic bladder tap

• Therapeutic: • Bladder catheterization

• Central line insertion and removal

• Chest tube insertion and removal

• Chest physiotherapy

• Mechanical ventilation

• Dressing change

• Gavage tube insertion

• Intramuscular injection

• Peripheral venous catheterization

• Tracheal intubation and extubation

• Tracheal suctioning

• Suture removal

• Ventricular tap

• Surgical: • Circumcision

• Others

Epidemiology

• Long term effects of untreated pain in the neonate: • Untreated pain leads to abnormal pain

pathways alteration in cerebral neuroanatomy ?developmental delays, ?emotional disorders, ?chronic pain d/o

• MRI of newborns (within first 7 days of life)

• fMRI’s of newborns: reveal neural activity of pain overlap with adult pain (33)

• Areas: primary somatosensory cortices, ACC, bilateral thalamus, insula

10

Complex Etiology

11

Genetic factors

Environmental triggers

Alterations in gene

expression

Complex Etiology: Genetic factors

• Strong genetic predisposition d/t marked familial aggregation (11-15)

• 1st-degree relatives of pts w/FM: 8-fold increase in risk of FM (16)

• Family members of FM pts: more likely to have lower pain threshold than general pop; often carry dx of other chronic pain syndromes: IBS, TMJ, and chronic HAs. (18)

• Current research: identified polymorphisms in genes assoc w/ serotonergic, dopaminergic, and catecholaminergic systems in pts w/ FM. (19)

12

Complex Etiology: Environmental triggers

Stressors involving: (1)

• acute pain

• motor vehicle traumas

• deployment to war

• infectious diseases

• psychological stress

13

Pathophysiology and Pathogenesis

• Hallmark of FM = Centralized Pain • Process: CNS amplifies sensory input across many organ systems(20-21)

• But... can’t r/o peripheral nociceptive input as a contributing factor (22-23)

• Patients will respond with pain to presence of touch or light pressure (i.e. allodynia), or even from normal noxious stimluli (i.e. hyperalgesia)

14

Pathophysiology and Pathogenesis 15



Central Sensitization

• A-delta fibers (large myelinated nociceptors) • transitory pain, easier to endure

• C-fibers (small unmyelinated nociceptors; free nerve endings) • chronic pain, harder to endure

• most numerous of sensory receptors and nociceptors

• bombardment of C-fibers in spinal cord proposed MOA FM central sensitization syndromes (chronically maintained and sympathetically maintained pain syndromes)

17


Central Sensitization: BOMBARDMENT OF C-FIBERS

18

• Required to processes influx of C-fibers

• Sprouting occurs (anatomic disorganized change in laminae)

Incr in NMDA receptors + glutamate

• Travels down peripheral receptors

• Ends at termination of C-fibers Incr Substance P production

• Incr receptor field in periphery

• Here: receptors more sensitive and more likely to depolarize “Wind Up”

Lowers

threshold

of C-fibers

Disorganizes

processing

of pain

Widened

receptor field

allows for A +

B to occur

A

B

C

C-fibers fire into IML Follow SNS


• fMRI studies: (27,28)

• Pain when stimulated by mild pressure or a heat stimulus

• Pain assoc w/activation in brain areas involved in pain processing

• Decr cortical thickness in the DLPFC, anterior insula, anterior cingulate cortex and somatosensory cortex (SI, SII) (35)

19

27


• Increased brain connectivity:

areas of increased pain

processing

• Decreased brain connectivity:

areas that attenuate pain

fRMI studies: (34)

Incr intrinsic DMN activity within

R. middle and ant. insula


• Proton spectroscopy studies: (29-32)

• Increases and decreases in neuromodulators of pain

• Tx for FM: alter these by targeting their receptors

21

Figure 1: CNS neurotransmission influencing pain (34)


• PET imaging studies: (44,45)

• Paradoxical incr in endogenous opioid activity and a decr in mu-opioid receptor availability

22


• Glial cell activation and central inflammation • modulate pain by:

• (1) harboring neurotransmitter receptors

• (2) releasing neuromodulators in response to pain

23

Acute effects:


• Glial cell activation and central inflammation • When chronically activated:

• pro-inflammatory cascade neurotoxicity

• ? explanation for central inflammatory process also involved in pathogenesis

• Glial cell modulating therapy:

• LDN

24

Chronic effects:


• Small fiber neuropathy • Defined: injury to peripheral nerves affecting small fibers

• Sx: burning, shooting, allodynia, hyperesthesia

• 2013 case-controlled study (46)

• FM pts: reduction in intraepidermal innervation and regeneration of C fibers

• Pts showed neuropathic pain

• Findings differed from healthy controls and unipolar depression w/o pain

• 2015 Retospective study (47)

• FM vs SFN and controls

• using EM: reduced axonal diameters of C-fibers (absent in SFN)

25

Distal nerve

pathology in

FM?


• SFN • Better hypothesis based on CNS theory (central sensitization):

• peripheral abnormalities d/t neuroplasticity or other co-morbid changes in chronic pain (e.g. deconditioning)?

• just a sequela of the syndrome?

• incidental finding?

26


• Raymond Perrin, DO, PhD • Hypothesis:

• insulin – biofeedback w/hypothalamus; HPA disrupted insulin fx disrupted

• poor filtering/drainage of CSF in BOTH head and spine toxins build up in CSF d/t lymph backflow

• Common findings seen clinically

• Treatment: massage, OMT

• Anecdotally tx worked, confirmed findings in Journal of medical engineering and technology

27


Osteopathic Perspective

5 Domains of Pathology in FM

29

Diagnosis

• Clinical Manifestation7: • Multifocal pain with low suspicion for a single etiology

• Amplified pain in other areas, usually earlier in life

• Symptoms suggestive of CNS origins

• Symptoms suggestive of global sensory hyper-responsiveness

• Pertinent past med hx:

• Co-morbid: chronic regional pain syndromes, rheumatic disease, psych

• Fam h/o FM

• Patient Self-Report Survey based on 2011 ACR Criteria Helpful for diagnosis

• Score of >/= 13 is consistent with FM.

30

Diagnosis: ACR 2011 modified fibromyalgia criteria(7) 31

Diagnosis: ACR 2011 modified fibromyalgia criteria(7) 32

Diagnosis

• Physical Exam Findings • Diffuse tenderness assessed by

tenderpoint exam

• Blood pressure cuff sensitivity from insufflation

• Low pain threshold to firm pressure of upper extremities

33

Diagnosis

• Perrin’s Signs: • head forward posture

• hyper mobility in cervical and lumbar region

• commonly thoracic problems

• incr in thoracic kyphosis and lordosis (T1-L2), mechanically SNS is over-irritated —> symptoms

• lymphatic varicosity

34

Diagnosis 35

Diagnosis 36

Diagnosis 37

Diagnosis 38

Diagnosis

• Perrin’s Symptoms: • “Perrin’s points” - tender

points (stars in image)

• Tenderness at celiac plexus

• Abnml Cranial Rhythm

39

Diagnosis

• “Fibro Fog” • Complaint: “I feel like I’ve been taking cold medicine

constantly”

• Symptoms: difficulty concentrating, finding words, holding conversations, feeling alert and remembering things

• Pathophysiology: (43)

1. Central processing abnormalities?

2. Morphologic abnormalities in the frontoparietal network?

3. Dysfunctional dopamine system?

40

Diagnosis

• “Fibro Fog” • Diagnosis: (43)

• Neurocognitive testing (1) effects of distraction on memory (2) speed of word retrieval

• Treatment: (43)

• Acknowledge its existence and reassure

• Co-occurence of ADHD (inattentive) and fibro is high common neurobiology and ?rationale for stimulants ongoing open-label trials (methylphenidate 10-60mg)

• Better sleep (FM often have insomnia)

• Best option thus far: CBT+physical activity+meds

41

Diagnosis

• Laboratory Tests • Blood Tests

• Results: non-specific

• If low suspicion for other causes: CBC, CMP, TSH, Vitamin D, ESR, and/or CRP.

• Rheum labs: (only if necessary): ANA and Rheumatoid factor.

• Ancillary Test

• Pts w/neuropathic signs (e.g. from SFN), or to r/o other causes: ENFD testing with skin punch biopsies

• Further W/U

• Imaging studies, muscle biopsies, EMGs, and mm enzyme assays

• Not required

42

Differential

• Somatic Symptom Disorder (SSD), specifier: with predominant pain (DSM-V) • Previously: Somatoform Disorders (DSM-IV)

• Myofascial Pain Disorder

• Inflammatory Myopathies

• Polymyalgia Rheumatica

43

Differential: SSD

Changes in new DSM-5: • Removal of DSM-IV disorders:

• somatization d/o, hypochondriasis, pain d/o, undifferentiated somatiform d/o many can now be diagnosed under SSD

• Somatization d/o required specific number of complaints from among 4 symptom groups

• SSD no longer requires this

• SSD does not require the presence of “medically unexplained symptoms” as an inclusion criteria

44

Differential

• CFS/ME • controversial: unique or on spectrum?

• overlap with FM: sleep, mood, pain, fatigue

• Differences:

• CFS/ME fatigue primary c/o

• FM pain primary c/o

• Tx:

• same for both

• so... doesn’t matter what you call it

• Dr. Perrin and OMT

45

Diagnosis: FM vs SSD

• It is difficult to differentiate the two b/c of similarities

• See functional somatic illnesses elsewhere in medicine, w/ overlapping sx and tx (CBT and meds) • Rheumatology: Fibromyalgia

• Infectious disease: Chronic fatigue syndrome

• Gastroenterology: Irritable bowel syndrome

• Neurology: Chronic headaches

• Cardiology: Noncardiac chest pain

• Urology: irritable bladder syndrome

• Gynecology: Vulvodynia and chronic pelvic pain

• Allergy: Multiple chemical sensitivity

• Oral surgeons: Temporomandibular joint syndrome

• Physical medicine: Myofascial pain syndrome

46


• Result of confusion? • Skepticism among the medical community that FM as a disease, truly exists

47


• What we know today: • FM is NOT SSD

• Need to establish diagnosis of FM – essential to tx (17)

• Key clinical differences to remember: • Pts usually do not focus on their condition to the exclusion of other life

interests, should not have markedly diminished social, sexual, and vocational functioning, and should not be profoundly physically deconditioned

48


• Result of incorrect dx: • Categorizing as having only SSD psychiatrization (25)

• Conversely, treating a patient for only FM pain ignoring sx of SSD and other psych factors poorer outcomes

49

Diagnosis: Solution

• A more nuanced method: • use a multidimensional approach:

• patient’s somatic, psychosocial, and functional status

• categorizing on a spectrum of severity (e.g. mild to moderate) along with co-morbidities (e.g. FM plus IBS) to individualize treatment (25)

50

Proposed method for diagnosing FM

Suspected FM begin a trial of treatment while evaluation of other co-morbidities (24)

51

CCF Program Model

Established FM diagnosis

Individualized treatments

(psychology/PT)

6 week FM Psychology Group +/- PT Group

(mild-moderate symptoms)

Monthly Relapse Prevention Group

CPRP (moderate-severe symptoms)

One Day Program (mild-moderate

symptoms)

Initial Assessment (Rheum or NCP)

Directing Treatment

52

Courtesy of Sara Davin, Psy.D, MPH

Chronic Pain Rehabilitation and FM

• Admission: • Pain: moderate-severe • Functional impairment: severe • Depression: moderate • Anxiety: severe

• Discharge: • Pain: mild-moderate • Functional impairment: moderate • Normalization of anxiety/depression • Improvements were clinically and statistically significant (p < .01)

Vij et al. Poster at American Pain Society (2014)

53


Do improvements last?

12 month follow-up

• 27.32% (n = 100) returned follow up surveys

• Pain: moderate

• Functional impairment: moderate

• Depression: moderate

• Anxiety: mild

• In comparison to admission, improvements remained clinically and statistically relevant (p < .01)

Vij et al. Poster to be presented at American Pain Society (2014)

54


Treatment

• No treatment alters pathogenesis of disease

• Focus on symptoms relief and functional restoration

Conservative Management

Oral pharmacotherapy

Non-invasive treatments

Invasive treatments

55

Treatment: Conservative Management

• *Patient education • Confirm FM label -- NO judgement

• Emphasize multimodal tx + active patient involvement

• *CBT • Pain based CBT in 1-1 sessions, groups, or via telemedicine

• *Graded Exercise • Aerobic exercise, strength training, stretching

• Nutrition • Weight loss (for those overweight or obese)

• Complementary medicine • Music: specifically water and wave sounds

• Other: Yoga, acupuncture, tai chi, chiropractic manipulation, myofascial release therapy, and osteopathic manipulation

* 3 best studies non-pharm tx for FM

56

Components of CBT-based Skill Building

• Education

• Coping skills

• Activity pacing

• Problem solving skills

• Assertiveness training

• Emotional modulation

• Relaxation training

• Sleep hygiene

• Relapse prevention

57


Treatment: Oral pharmacotherapy

Overarching goal of oral pharmacotherapy:

excitatory neurotransmission via:

inhibitory neurotransmission via:

58

glutamate,

substance P, and

nerve growth

factor activity

norepinephrine,

dopamine, and

GABA activity

Facilitate pain transmission

Inhibit pain transmission

Treatment: Oral pharmacotherapy 59

Figure 1: CNS neurotransmission influencing pain (34)


TCAs and

SNRIs

•Amitriptyline: 10-70mg qhs

Cyclobenzaprine: 5-20mg qhs

•Duloxetine: 30-120mg qd (FDA approved)

Milnacipran: 100-200mg qd (FDA approved)

Venlafaxine XR: 75-225mg qd

Gabapentinoids and

GABA agents

•Gabapentin: up to 3600mg qd in divided doses

•Pregabalin: up to 600mg qd in divided doses (FDA approved)

•Gamma-hydroxybutyrate (sodium oxybate): 4.5-6.0 mg qd in divided doses

60

First line – Level 1A

evidence


SSRIs • Fluoxetine

• Sertraline

• Paroxetine

Cyclobenzaprine

• Monotherapy: 10-40mg qd

• Combination: cyclobenzaprine 10mg qd + fluoxetine 20mg qd

61

Second line –

no convincing

evidence


Opioids (full and weak opioid agonist): • History:

• Nidus: very poor 1986 retrospective review of 38 pts

• Fact:

• poor outcomes not recommended

• Unfortunately

• (1) use in FM is widespread, (2) those given opioids were unlikely to receive evidence based pharmacotherapy,(3) less likely to respond well opioids (41-42)

• Interestingly:

• patients have elevated CSF levels of endogenous opioids (38) + decreased binding capacity to mu-opioid receptors in pain areas of brain (39) ? account for poor outcomes (40)

62


• Low dose naltrexone: 4.5mg qhs (36)

• Promise in treating chronic pain conditions that involve inflammatory processes but FM doesn’t have inflammation in FM??

• Rationale: FM may involve chronic glial activation and subsequent production of pro-inflammatory cytokines

• Benefits: low SE profile, no abuse potential, low cost (on avg, $35/month vs >$100/month for conventional oral meds)

• Synthetic Cannabinoids (37)

• Nabilone: 0.5mg qhs to 1.0mg bid

• Limited available data with studies showing a non-significant trend for analgesia, but they may be a consideration in those with significant sleep disturbances

63

Future treatment options: promising results, but lack sufficient data

Treatment: Other treatments

• Non-invasive: • rTMS

• rTDCS and HD-rTDCS

• Hyperbaric O2 (prelim study)

• TENS unit (mixed results)?

• OMT and Soft Tissue Techniques

• Invasive:

• ONS

• TP injections?

64

Treatment: Non-invasive treatments

• rTMS and HD-rTDCS • Target: left primary motor cortex and dorso-lateral

prefrontal cortex

• Study outcomes: (48,49)

• reduction in FM pain and effects outlasting the duration of stimulation

• outcomes similar to medications

• Benefits: minimal SE (most common: transient HA and scalp irritation)

• Studies: • on-going phase-II open label trial for HD-rTDCS (50)

• more targeted, more tolerable, higher specificity

65

TD

CS

TM

S

Treatment: Non-invasive treatments

• ESWT

• Concept: high energy acoustic waves (i.e. shock waves) delivers mechanical force

• Use: MSK pain (e.g. MPD)

• How it works in MPD (MOA still elusive)

• Shock waves elicit referred pain (from TPs) induces energy stimulates healing through inflammation and incr blood flow to damaged tissues promote healing

• In FM: (only 1 study to date) improvements 3-mo post tx, no SE (51)

• improved: VAS and algometer

• 2000 pulses in 5 sessions

• ?effective adjunct early in d/o

66

Treatment: Invasive treatments

• ONS

• Use: migraine headaches, chronic primary HAs

• MOA: unclear

• SE: high risk of complications d/t invasive

• 2007 study (lacked placebo; co-morbid chronic HAs) (52)

• C2 scalp area; VAS , BDI, QOL (SF-36)

• HAs, widespread bodily pain, mood, and fatigue improved

• 2013 study (double-blind, placebo controlled) (53)

• subsensory threshold stimulation

• psych d/o excluded (except mild depression), no HAs, intractable to PT, meds, psych therapy

• decr (40-60%) in pain 6 mo post-implant (VAS and PCS, not BDI), decr in tender points

67

Treatment: Perrin’s Plan

• cranial massage

• stimulating blood blood flow in shoulders with cold and heat

• draining motion down nose

• working fingers up chest

• rotating body around upper waist

• rotating shoulders

• marching up and down, shaking arms back and forth

• avoid stimulants - coffee and etoh

• watch for bad posture

• keeping spine straight while sleeping; pillow between knees

• proper sleep

68

Treatment: Perrin’s Plan 69

• Video excerpt

Treatment: OMT Overview

• Counterstrain of various bilateral tenderpoints assoc w/FM

• Rib raising

• Myofascial Release

• Muscle energy

• Balance Ligamentous Tension

• Facilitated Positional Release

• TMJ treatments

70

Treatment: OMT Specifics

• Seated lumbosacral functional technique

• Seated lumbosacral functional technique

• Sidelying rib functional technique

• Seated upper thoracic spine muscle energy technique

• Seated or supine diaphragm myofascial release technique

• Supine cervical functional and strain/counterstrain techniques

• Supine TMJ muscle energy techniques

71

Take Home Points

• FM-like symptoms described in texts dating back 100s of years

• First given a name in the 1600’s; 2007 FDA approved 1st drug

• Very common in rheum practices

• Onset between 35-55yo

• Symptoms increase with age, but see in children also

• Life long sx – mimic other pain d/o

• Defined on a spectrum of central sensitization d/o

• Active research - glial cell activation, central inflammation, and small fiber neuropathy, LDN, TMS, TDCS, ECWT, ONS

• Many options for management

• Left untreated – devastating for pt, provider and health care system

72

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http://www.ncbi.nlm.nih.gov/pubmed/24737367




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• Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58(1):26–35.

• Smith HS, Harris R, Clauw D. Fibromyalgia: an afferent processing disorder leading to a complex pain generalized syndrome. Pain Physician 2011;14 (2):E217-45.

• Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis Rheum 1990; 33:160–72.

• www.uptodate.com.arktos.nyit.edu/contents/clinical-manifestations-and-diagnosis-of- fibromyalgia-in-adults?source=search_result&search=fibromyalgia&selectedTitle=2%7E127

• www.uptodate.com.arktos.nyit.edu/contents/initial-treatment-of-fibromyalgia-in- adults?source=search_result&search=fibromyalgia&selectedTitle=3%7E127

• Gamber R., Shores J., Russo D., Jimenez C., Rubin B. Osteopathic manipulative treatment in conjunction with medication relieves pain associated with fibromyalgia syndrome: Results of a randomized clinical pilot project. JAOA 2002; Vol 102: No 6. —> This study found OMT combined with standard medical care was more efficacious in treating FM than standard care alone.

• Seffinger M. Osteopathic Approach to the Patient with Fibromyalgia. American Osteopathic Association Annual Scientific Convention and Medical Education Conference. 2010

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Online Resources*

• http://www.niams.nih.gov/Health_Info/Fibromyalgia/fibromyalgia_ff.asp

• http://www.mayoclinic.org/diseases-conditions/fibromyalgia/in-depth/fibromyalgia/art-20048097

• https://my.clevelandclinic.org/health/diseases_conditions/hic_Fibromyalgia

• http://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Fibromyalgia

• http://www.fmaware.org/about-fibromyalgia/

*Accessed 02/04/2017

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http://www.niams.nih.gov/Health_Info/Fibromyalgia/fibromyalgia_ff.asp



http://www.mayoclinic.org/diseases-conditions/fibromyalgia/in-depth/fibromyalgia/art-20048097







https://my.clevelandclinic.org/health/diseases_conditions/hic_Fibromyalgia

https://my.clevelandclinic.org/health/diseases_conditions/hic_Fibromyalgia

http://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Fibromyalgia









http://www.fmaware.org/about-fibromyalgia/



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Fibromyalgia NOVEL THERAPIES, AND OMT · 2018-10-08 · Complex Etiology: Genetic factors •Strong genetic predisposition d/t marked familial aggregation (11-15) •1st-degree relatives