Download Fibromyalgia 2013:

Fibromyalgia 2013:
State – of – the - art and future
directions
Jacob Ablin, M.D.
Tel Aviv Sourasky Medical Center
Rheumatology Institute & Fibromyalgia Clinic
1
What is Fibromyalgia?
How fibromyalgia tics…
Fibromyalgia and Overlapping Disorders
Yunus, MB: Fibromyalgia and Overlapping Disorders:
The Unifying Concept of Central Sensitivity Syndromes. Sem Arthritis Rheum 2006
ACR 1990 Fibromyalgia
classification
Criteria
Widespread* pain (3 months at least)
 Tender points – 11/18

* i.e. involving upper & lower limbs + spine
5
Assessment of tenderness with a manual
dolorimeter
6
7
‫הבעיות עם נקודות הרגישות‪...‬‬
‫‪‬‬
‫‪‬‬
‫‪‬‬
‫‪‬‬
‫‪8‬‬
‫הדרך הכי פחות אמינה למדוד רגישות )מאד‬
‫מושפע מרמת החרדה של הנבדק(‬
‫מכוון את תשומת הלב אל השרירים והגפיים‪,‬‬
‫למרות שלא שם הבעיה‬
‫גורם לאבחון יתר אצל נשים‬
‫המספר ‪ 11‬הוא שרירותי‬
Distinct, but not Dichotomic…




Fibromyalgia - the paradigmic central pain condition
Many patients suffer from “Primary” or “Pure”
fibromyalgia
These patients have a typical clinical presentation,
course, genetic background, and response to
treatment
At the same time, Fibromyalgia is part of a spectrum
characterized by central sensitization, and
“Fibromyalgianess” can be identified (and treated!) in
many other patient populations
New FMS diagnostic criteria
(Arthritis care & research, 5.2010)

1.
2.
3.
3 conditions must be met:
Widespread Pain Index (WPI) ≥7 and
symptom Severity (SS) scale score ≥5 or WPI
3-6 and SS ≥9
Symptoms present at similar level for three
months
The patient does not have a disorder that
would otherwise explain the pain
10
Fibromyalgia diagnostic criteria
Criteria
A patient satisfies diagnostic criteria for Fibromyalgia if the following
3 conditions are met:
1. Widespread pain index (WPI) ≥ 7 and symptom severity (SS) scale score ≥ 5
or WPI 3–6 and SS scale score ≥ 9.
2. Symptoms have been present at a similar level for at least 3 months.
3. The patient does not have a disorder that would otherwise explain the pain.
WPI
WPI: note the number areas in which the patient has had pain over the last week.
In how many areas has the patient had pain? Score will be between 0 and 19.
• Shoulder girdle, left
• Shoulder girdle, right
• Upper arm, left
• Upper arm, right
• Lower leg, left
‫ מקבל נקודה‬19 -‫כל איזור כואב מבין ה‬
19
-‫ ל‬0 ‫ערך זה נע לכן בין‬
‫ • הציון בעבור‬Upper back
• Hip (buttock, trochanter), left
• Jaw, left
• Hip (buttock, trochanter), right
• Upper leg, left
• Upper leg, right
• Lower arm, right
• Jaw, right • Lower back
• Chest
• Neck
• Abdomen • Lower arm, left
• Lower leg, right
Fibromyalgia diagnostic criteria
Criteria
A patient satisfies diagnostic criteria for Fibromyalgia if the following
3 conditions are met:
1. Widespread pain index (WPI) ≥ 7 and symptom severity (SS) scale score ≥ 5
or WPI 3–6 and SS scale score ≥ 9.
2. Symptoms have been present at a similar level for at least 3 months.
3. The patient does not have a disorder that would otherwise explain the pain.
• Fatigue
• Waking un-refreshed
• Cognitive symptoms
For each, indicate level of severity over the past week using:
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: pervasive, continuous, life-disturbing problems
Considering somatic symptoms in general, indicate whether the patient has:
0 = no symptoms ; 1 = few symptoms ; 2 = moderate number of symptoms ; 3 = a great deal of symptoms
‫‪Fibromyalgia diagnostic criteria‬‬
‫‪3-6‬‬
‫‪>7‬‬
‫‪+‬‬
‫‪+‬‬
‫‪>9‬‬
‫‪>5‬‬
‫‪WPI‬‬
‫כל איזור כואב מבין ה‪ 19 -‬מקבל נקודה‬
‫הציון בעבור ערך זה נע לכן בין ‪ 0‬ל‪19 -‬‬
‫)‪Symptom severity scale (SS‬‬
‫סיכום מידת החומרה של שלושת הסימפטומים‬
‫)עייפות‪ ,‬שינה לא מרעננת והפרעות קוגנטיביות(‬
‫)‪ 0‬עד ‪ 3‬לכ"א‪ ,‬סה"כ בין ‪ 0‬ל‪ (9 -‬מתווסף לסיכום מידת החומרה‬
‫של הסימפטומים הסומאטיים* )‪ 0‬עד ‪ 3‬סה"כ(‪.‬‬
‫לכן‪ ,‬סיכום ה‪ SS -‬נע בטווח של ‪ 0‬עד ‪ 12‬סה"כ‪.‬‬
‫קבלת כל אחד משני הצירופים הנ"ל מאפשר זיהוי נכון של פיברומיאלגיה )על פי‬
‫הקריטריונים של ה‪ (ACR -‬וזאת‪ ,‬מבלי לבדוק נקודות רגישות!‬
‫*סימפטומים סומאטיים יכולים להיות ‪ , IBS -‬כאבי ראש‪ ,‬דיכאון‪ ,‬עצירות‪ ,‬עייפות‪ ,‬סחרחורות‪ ,‬תחושת רדימות‪/‬דקירות וכו'‪...‬‬
2011modified criteria




WPI – unchanged from 2010 criteria
Symptom Severity Score – Fatigue, Waking
un-refreshed, Cognitive symptoms
Plus - the sum of the number of the following
symptoms occurring during the previous 6
months: headaches, pain or cramps in lower
abdomen, and depression (0–3).
The final score is between 0 and 12.
14
Old vs. New Fibromyalgia
criteria
ACR 1990 criteria: classification criteria (not meant
for clinical diagnosis)
 Physical examination + tender point testing
mandatory
2011 criteria: Diagnostic criteria
 Physical examination not mandatory
 Spectrum of symptoms recognized, including
fatigue, cognitive problems and many, many
more
15
What Causes Fibromyalgia?



Genetics
“Triggers”
Mechanisms
Relationship between physiological and
psychological factors
 Disordered sensory processing
 Autonomic/neuroendocrine dysfunction

16
Genetics of Fibromyalgia

Familial predisposition


>8 odds ratio (OR) for first-degree relatives, and
much less familial aggregation (OR 2) with major
mood disorders
Genes that may be involved
5-HT2A receptor polymorphism T/T phenotype
 Serotonin transporter
 Dopamine D4 receptor exon III repeat
polymorphism
 COMT (catecholamine o-methyl transferase)

What Causes Fibromyalgia?



Genetics
“Triggers”
Mechanisms
Relationship between physiological and
psychological factors
 Disordered sensory processing
 Autonomic/neuroendocrine dysfunction

18
“Stressors” Capable of Triggering These
Illnesses (Supported by Case-Control Studies)








Peripheral pain syndromes
Infections (eg, parvovirus, EBV, Lyme disease,
Q fever; not common URI)
Physical trauma (automobile accidents)
Psychological stress/distress
Hormonal alterations (e.g., hypothyroidism)
Drugs (statins, aromatase inhibitors)
Vaccines
Certain catastrophic events (war, but not
natural disasters)
Clauw et al. Neuroimmunomodulation. 1997;4:134-153; McLean et al. Med Hypotheses.
2004;63:653-658.
19
What Causes Fibromyalgia?



Genetics
“Triggers”
Mechanisms
■
Augmented pain and sensory amplification
identifiable via:
■
■
■
Experimental pain and sensory testing
Functional neuroimaging
In part due to:
■
Alterations in CNS levels of neurotransmitters involved in
controlling descending facilitatory vs. inhibitory pathways
20
Neural Influences on
Pain and Sensory Processing
Inhibition
Facilitation
■
■
Descending antinociceptive pathways
■
Glutamate and EAA
■
■
Substance P
Serotonin
(5HT2a, 3a)
+
Norepinephrineserotonin (5HT1a,b),
dopamine
■
Nerve growth factor
■
■
CCK
■
■
Opioids
GABA
Cannabanoids
■
Adenosine
Specific Underlying
Mechanisms in Fibromyalgia

Decreased descending
analgesic activity
Absent or attenuated
DNIC in FM, IBS, OA,
and many other pain
states1-3
 Brainstem activations with
conditioning stimulus seen
in controls but not in FM
patients4

1. Kosek and Hansson. Pain. 1997;70:41-51. 2. Julien et al. Pain. 2005;114:295-302.
3. Wilder-Smith and Robert-Yap. World J. Gastroenterol. 2007;13:3699-704. 4. Gracely et al. Arthritis Rheum. 2006 (abstract).
Increased Temporal summation





Temporal summation of second pain (TSSP) results
from repetitive stimulation of peripheral C-fibers
Reflects summation mechanisms of dorsal horn
neurons (i.e. windup)
Short term enhancement of C fiber-evoked responses
that decay rapidly after the end of stimulation
Maintained enhancement is indicative of central
sensitization
Maintained enhancement of heat stimuli is increased in
FMS patients and after sensations are prolonged
23
Fibromyalgia Cerebrospinal Fluid
Substance P
Normals
Substance P
(ng/ml)
50
Fibromyalgia Syndrome
40
30
20
10
0
Vaeroy 1 Russell 2
Welin 3
Bradley 4
1. Vaeroy et al. Pain. 1988;32:21-6. 2. Russell et al. Arthritis Rheum. 1994;37:1593-601.
3. Liu et al. Peptides. 2000;21:853-60. 4. Bradley and Alarcon. Arthritis Rheum. 1999;42:2731-2.
fMRI in Fibromyalgia and
Related Conditions



Objective evidence of augmented pain
processing in FMS
Role of depression in pain processing in FMS
Role of cognitive factors in pain processing in
FMS
Locus of control
 Catastrophizing


Objective evidence of augmented pain
processing in idiopathic chronic low back pain
25
Pain Intensity
Stimuli
and
Responses
During
Pain
Scans
14
12
10
8
6
Fibromyalgia
4
Subjective Pain Control
Stimulus Pressure Control)
2
0
1.5
2.5
3.5
4.5
Stimulus Intensity (kg/cm2)
IPL
SII
STG=superior temporal gyri, SI=primary somatosensory cortex,
SII=secondary somatosensory cortex, IPL=inferior parietal lobule.
SI
SI (decrease)
STG, Insula, Putamen
Cerebellum
26
Gracely. Arthritis Rheum. 2002;46:1333-1343.
What Causes Fibromyalgia?



Genetics
“Triggers”
Mechanisms
Relationship between physiological and
psychological factors
 Disordered sensory processing
 Autonomic/neuroendocrine dysfunction

27
Management of Fibromyalgia (and other
central pain syndromes)
•
•
•
•
Pharmacotherapy
Antidepressants
Analgesics
Anticonvulsants
Cardiovascular
exercise
Treatment Approaches
Alternative/ complementary
• Acupuncture
• Balneotherapy / Hydrotherapy
• Tai – Chi
• Biofeedback
Cognitive behavioural
therapy
Patient education
Goldenberg et al. JAMA. 2004;292:2388-2395; Clauw and Crofford. Best Prac Res Clin Rheumatol. 2003;17:685-701.
Non-Pharmacological Therapies

Strong evidence



Education
Aerobic exercise
Cognitive behavior therapy

Modest evidence

Strength training
 Hypnotherapy, biofeedback, balneotherapy
Weak evidence - Acupuncture, chiropractic, manual and
massage therapy, electrotherapy, ultrasound
No evidence : tender (trigger) point injections, flexibility
exercise


Goldenberg et al. JAMA. 2004;292:2388-2395.
29
Exercise


Aerobic exercise universally beneficial; tolerance,
compliance, adherence are biggest issues
To maximize benefits:
Begin several months after pharmacologic therapy
 Begin with low-impact exercises; avoid strength
training until late
 Both physician and patient should consider this as a
“drug”


Less evidence supporting strengthening,
stretching
30
Cognitive Behavioral Therapy



A program designed to teach patients
techniques to reduce their symptoms, to
increase coping strategies, and to identify
and eliminate maladaptive illness behaviors
Shown to be effective for nearly any chronic
medical illness
Not all CBT is created equally; very
dependent on therapist and program
31
Pharmacological Therapies

Strong evidence



Dual reuptake inhibitors such as
 Tricyclic compounds (amitriptyline, cyclobenzaprine)
 SNRIs and NSRIs (venlafaxine, milnacipran,
duloxetine)
Anticonvulsants (e.g. gabapentin, pregabalin)
Modest evidence
Tramadol
 Selective serotonin reuptake inhibitors (SSRIs)
Weak evidence - Growth hormone, 5-hydroxytryptamine,
tropisetron, S-adenosyl-L-methionine (SAMe)
No evidence - Opioids, corticosteroids, nonsteroidal antiinflammatory drugs, benzodiazepine and nonbenzodiazepine
hypnotics, guanifenesin



32
Modified from Goldenberg et al. JAMA. 2004
Recommended Approach



Identify and treat “peripheral” pain generators”
For patients who need or want medications, start
with low doses of tricyclic antidepressants
(amitriptyline); start low, go slow
If patient tolerates TCA, but symptoms persist
Add mixed reuptake inhibitor (eg, venlafaxine,
duloxetine)
or SSRI (may need high doses)
 For additional analgesic effect add pregabalin,
gabapentin, tramadol


Aggressively introduce non-pharmacological
therapies
33
Clauw et al. Best Pract Res Clin Rheumatol. 2003;17:685-701 (B).
Identify and Treat Central Pain
or “Fibromyalgia-ness”
This is primarily a neural disease and
“central” factors play a critical role
■
■
This is a polygenic disorder
■
■
Lack of sleep or exercise increase
pain and other somatic sx, even in
normals
■
How FM patients think about their
pain (cognitions) may directly
influence pain levels
Treatments aimed at the periphery
(i.e., drugs, injections) are not very
efficacious
■
There is a deficiency of
noradrenergic-serotonergic activity
and/or excess levels of excitatory
neurotransmitters
■
■
■
There will be subgroups of FM
needing different treatments
Drugs that raise norepinephrine and
serotonin, or lower levels of excitatory
neurotransmitters, will be efficacious
in some
■
Exercise, “sleep hygiene,” and other
behavioral interventions are effective
therapies for biological reasons
Cognitive therapies are effective in FM
and have a biological substrate
Symptoms of Pain,
Fatigue, etc.
■
Nociceptive processes (damage or
inflammation of tissues)
■ Disordered sensory processing
Dually
Focused
Treatment
Pharmacological
therapies to improve
symptoms
■
Functional Consequences
of Symptoms
Increased distress
■ Decreased activity
■ Isolation
■ Poor sleep
Maladaptive illness behaviors
■
■
Clauw and Crofford. Best Pract Res Clin Rheumatol. 2003;17:685-701.
■
Nonpharmacological
therapies to address
dysfunction
Opiod antagonists




Opiod medications are ineffective in
management of FMS
Imaging has demonstrated decreased central
µ-opioid receptor availability in FMS
Elevated endogenous opiods may be responsible
for increased pain sensitivity - endogenous
opiod – induced hyperagesia
Opiod antagonists are a novel possibility for
management of FMS
36


low dose naltrexone, an opiod antagonist,
significantly improved pain and fatigue in FMS
Naltrexone may in fact not act as a opiod
antagonist, but rather as an anti – inflammatory
agent, attenuating pro-inflammatory activity of
immune competent microglia in the CNS
37
Guidelines for the diagnosis
and treatment of Fibromyalgia
Israeli Fibromyalgia group & Israeli
Rheumatolgy association
Guideline Purpose


To develop practical and evidence- based
guideline recommendations for the Israeli health
care system, regarding the diagnosis and
treatment of Fibromyalgia
Increase awareness, promote earlier recognition,
avoid unnecessary, costly, unpleasant and
dangerous diagnostic procedures, and
inappropriate treatment
Israeli Guidelines
Diagnosis: History


History of widespread pain after ruling out
possibility of inflammatory or other illness
explaining symptoms
Nonetheless, fibromyalgia can co-exist with
additional inflammatory / metabolic disorders
Specific points on history:




Pain involving muscles, joints, connective tissue
and both axial and appendicular skeleton
Typical sleep – related complains, e.g. difficulty
falling asleep, frequent waking, waking unrefreshed
Chronic daytime fatigue
IBS - like symptoms, e.g. diarrhea /
constipation, bloating, abdominal pain etc.
Physical examination



Crucial to rule out alternative causes of pain e.g.
arthritis, osteoarthrotis, spinal stenosis,
neurological disorder etc.
Although new ACR criteria do not require
physical examination, sound clinical evaluation
does.
Tenderness should be assessed, although a
formal tender point count is no longer required
Lab workup






No specific lab markers currently available
Purpose of Labs – rule out alternative diagnoses
Labs ordered will be influenced by results of
history and physical examination BUT at a
minimum the following should be ordered:
CBC, Renal & liver function, Ca / phos, CPK
ESR / CRP
TSH, Vitamin D
Serological tests



ANA, RF etc – at physician's discretion,
depending on presence of indicative signs /
symptoms
Yet, early symptoms of connective tissue
disorders may be subtle (e.g. fatigue) so these
test may often be justified
Genetic markers (HLA-B27, HLA-B51, FMF)
should only be ordered based on clinical
suspicion
Education




Explaining nature of the disorder on initial
encounter is critical to establish long – term
therapeutic relationship, decrease anxiety
Education per se often leads to significant
improvement in quality of life, reduced health
care utilization, improved coping and function
Family members encouraged to attend visits,
hear explanations and thus become more
supportive
Written material, web sites, are helpful
Specific points to discuss





Non – progressive, non – deformative character
of fibromyalgia
Symptoms often chronic
Normal life span
Emphasis on maintaining function, activity,
social role, work etc.
Initial evaluation of levels of exercise
Treatment of Fibromyalgia



Discussing goals of treatment and setting
realistic expectations is crucial
Treatment is multi – modal and must include a
combination of pharmacological and non –
pharmacological modalities
Non – pharmacological interventions (e.g.
exercise, CBT) are highly effective, but require
active patient participation (which is good!)
Pharmacological treatment




Not every patient necessarily needs / wants
medications
Patients are sensitive, so – start low and go slow
Medications affecting CNS pain processing are
required
Medications can decrease pain, improve sleep
and other core symptoms
Personalized treatment





Must pay attention to specific characteristic of
each patient:
If clearly depressed – prefer medication with
anti – depressant effect
Sleep disorders are more improved by some
medications than others
Obesity is an issue with some meds more than
others etc.
Co- morbidities, medications,
pharmacogenetics…
Amitriptyline (Elatrol) - Strong
evidence






Old tricyclic medication
Used in Fibromyalgia at low doses
Improves sleep and pain
Efficacy demonstrated in a number of (relatively
old) studies
Recommended initial dose – 10 mg at bedtime
Dose can be increased to 25 mg after a few
weeks
SNRI medications (strong
evidence)





SNRI shown to be more efficacious in
fibromyalgia, compared with SSRI’s
Duloxetine (Cymbalta) :
Evidence of efficacy in large, double – blind,
placebo controlled studies
Works both in patients with and without
depression
Treatment starts at 30 mg, increase to 60 mg





Milnacipran (Ixel)
Large RCTs (over 1000 patients)
Significant improvement in pain. Fatigue, global
assessment
Dose – 100-200 mg/day
FDA approved for fibromyalgia, registered in
Israel for depression.
Anti convulsants (strong
evidence)





Pregabalin and Gabapentine – act as alpha-2ligands
Pregabalin (Lyrica) :
First FDA approved fibromyalgia med
Efficacy proven in large RCTs (over 3000
patients)
Meta-analysis – Significant improvement in
quality of life, pain, sleep at 300-450 mg/day
Tramadol (Moderate evidence)



Analgesic medication with mixed mechanism of
action: weak opiod, SNRI and centrally acting
Often combined with other analgesic
(paracetamol)
Moderate efficacy demonstrated in fibromyalgia
SSRI




Effective for anxiety and depression
Weak evidence for efficacy in fibromyalgia
Less selective SSRI (Fluoxetine ) more effective
than newer, highly selective agents (e.g.
citalopram)
Can be combined with more adrenergic agents,
e.g. Amitriptyline
Medications Not recommended





NSAIDS
Opiods
Steroids
Benzodiazepines
Guaifenesin
Stratified approach to the
management of Fibromyalgia:
Education regarding nature of disorder, prognosis, coping
Identification of local pain – generators (bursitis, tendinitis etc)
Start low-dose Tricyclic medication (e.g. Amitriptyline 10mg)
Actively encourage non – pharmacological treatment: exercise, CBT, hydrotherapy, alternative
(meditative – movement) treatment
Re-evaluate after 12-24 weeks. Consider increasing dose or switching:
Pregabalin
(e.g. If Insomnia remains major issue )
Douloxetine, Milnacipran
(e.g. if Depression remains a major issue)
As necessary consider SOS pain medication (Tramadol)
However we define fibromyalgia, FMS patients are all
around us, and suffering…
The Fibromyalgia concept has helped us study central pain,
replace chaos with order and explain the condition to patients
While Fibromyalgia may not be a pure YES – NO situation, and many
patients may have “some” fibromyalgianess, a large population do in fact
suffer from pure, straight – forward fibromyalgia per - se
Increasing knowledge regarding pathogenesis, genetics etc will
allow us to better sub – classify patients and direct
individualized treatment
At the same time Fibromyalgia is in many aspects the heart of
“Rheumatism” and all rheumatologists should feel comfortable
identifying, diagnosing and treating fibromyalgia, so they can address
central sensitization in all there patients