FIBROMYALGIA

KRT Lucas Meliala

Guru Besar Luar Biasa
Bagian Ilmu Penyakit Saraf
Fakultas Kedokteran Universitas Gadjah Mada,
Yogyakarta

Pendidikan :

Curriculum Vitae
Nama
Tempat/tanggal lahir

:
:

Alamat
Telepon
Fax.
Mobile
E-mail

:
:
:
:
:

Prof. dr. KRT. Lucas Meliala, SpKJ, SpS(K).

Membang Muda (Sumut),
22 September 1941
Jl. Nagan Lor 70, Jogjakarta
(0274) 450758
(0274) 374052
0815 687 0584
[email protected]

Lulus Dokter tahun 1969,

alumnus FK-UGM
Lulus Spesialis Saraf & Jiwa tahun 1974
alumnus FK-UI, FK-UGM, FK Unair
Pekerjaan :
Staf Fakultas Kedokteran UGM
bagian IP Saraf dan Jiwa sejak
tahun 1968 sampai sekarang
Organisasi :
1999-2007 :
Ketua Pokdi Nyeri Perdossi
Anggota IASP, ENS
Ketua Governing board IPS

What is fibromyalgia?
Common chronic widespread pain condition
characterized by increased pain sensitivity the
extreme end of a spectrum of abnormal pain
perception/processing1
Patients may present with a wide range of other
symptoms, eg:

Sleep disturbance
Fatigue
Tenderness
Stiffness
Mood disorders
Flu-like aching
Headache

1. Wolfe F, et al. Arthritis Rheum 1995;38:19-28.

Part Of Human Life

JASMANI
JIWA
ROH

Klasifikasi Nyeri

NOCICEPTIVE PAIN
Noxius Pheripheral Stimuli

Pain
Autonomic Response
Witdrawal Reflex

Heat

Nosiseptif

Cold
Intense
Mechanical
Force

Brain
Nociceptor
sensory neuron

Heat
Spinal cord

Cold

Adaptif

INFLAMANTORY PAIN
Spontaneous Pain
Inflammation
Pain Hypersensitivity

Macrophage

Inflamasi

Reduced Threshold : Aliodyna

Increased Response : Hyperalgesia

Mast Cell
Neutrophil
Granulocyte

Tissue Damage

Brain
Nociceptor
sensory neuron
Spinal cord

Nyeri

NEUROPATHIC PAIN
Spontaneous Pain
Pain Hypersensitivity
Brain

Neuropatik

Peripheral Nerve
Damage
Spinal cord Injury

Maladaptif

FUNCTIONAL PAIN
NOCICPTOR

Fungsional

Spontaneous Pain
Pain Hypersensitivity
Brain

NOCICPTOR
Normal Peripheral
Tissue and Nerves
NOCICPTOR

Abnormal Central
Processing

FUNCTIONAL PAIN
Spontaneous Pain
Pain Hypersensitivity
Brain

Normal Peripheral
Tissue and Nerves

Abnormal Central
Processing

PENYAKIT, KESAKITAN, ATAU

KEDUANYA
BERU

AM E

Tanpa Ulkus
( tidak luka)

Ulkus (luka)

Nyeri perut
fungsional
yang kronik

Penyakit dan
kesakitan
Penyakit
tanpa
kesakitan

SAKIT

Kesakitan
tanpa
penyakit

SAKIT

Fibromyalgia symptoms

Pain, fatigue and sleep disturbance are present in 86%

of patients
100%

100

96%
86%
72%

80

60%

60

56%

52%

46%

42%

41%
32%

40

20%

20
0
Muscular
pain

US data

Fatigue

Insomnia

Joint
pains

Headaches

Restless Numbness Impaired

legs
memory
and
tingling

Leg
Impaired Nervous- Depression
cramps concenness
(major
tration
depression)

ACR Fibromyalgia Diagnostic Criteria. National Fibromyalgia Research Association Web site.
Available at: www.nfra.net/Diagnost.htm. Accessed October 18, 2007.

Quality of life in patients with

fibromyalgia

Decrease in health status in fibromyalgia may exceed that of other

painful conditions
FM (n=43)

Mean SF-36 score

100

OA knee (n=547)

Osteoporosis (n=280)

RA (n=156)

80
60
40
20
0
Physical
function

Higher score = better status/function

Survey of Dutch general population

Physical
role
limitation

Bodily
pain

General
health
perception

Vitality

Social
function

Emotional
role

Mental
health

Picavet HS, Hoeymans N. Ann Rheum Dis 2004;63:723-729. Hoffman DL, Dukes EM. Int J Clin Pract 2008;62:115-126.

Pathogenesis of fibromyalgia
The pathogenesis of fibromyalgia is unknown
Emerging science indicates that multiple factors may
be involved in the pathogenesis of fibromyalgia;
however, central sensitization is currently the leading
theory

Mechanisms of central sensitization

Disordered sensory processing
Increased levels of neurotransmitters/biogenic amines
Other mechanisms: Autonomic/neuroendocrine dysfunction

Gur and Oktayoglu, Curr Pharma Des 2008;14:1274-1294

Martinez-Lavin, Arth Res and Ther 2007;9:216

Stress is life and life is stress

- Hans Selye

Stressors are forces that disturb homeostasis

Acute physical, chronic physical, psychological,
anticipatory

Counterbalanced by adaptive forces

Central adaptation, peripheral adaptation

Hypothalamic-pituitary-adrenal (HPA) axis

and autonomic nervous system (ANS) are
critical components of the coordinated
physiologic response to stress
Physical, behavioral, and psychological
symptoms linked to HPA axis and ANS
abnormalities

Stressors
Higher
cortical
centres

Pituitary
Gland
CRH

ACTH

Autonomic nervous
system
Adrenal
cortex

sympathetic

Glucocorticoids

Adrenal
medulla

Epinephrine
Norepinephrine

Knowles et al., 2009

Modifikasi Meliala, 2009

parasympathe
tic

Immune
system

ENS

Subcortical
region inc.
hypothalam
us

Brain stem nucle

Descending
spinal
pathways

Pathogenesis of fibromyalgia: The neurotransmitter substance P

Elevated substance P demonstrated in CSF of fibromyalgia

patients
CSF levels of substance P in
fibromyalgia patients vs
healthy control subjects
measured in 3 separate
clinical studies

Substance P Concentration
(fmol/mL)

45

p<0.001

p<0.001

40
35
30

Fibromyalgia patients

25

p=0.03

20

Healthy control subjects

15
10
5
0

Russell
1994

Russell
1995

Bradley
1996

n numbers:
Russell 1994Fibromyalgia=32, Control=30
Russell 1995Fibromyalgia=24, Control=24
Bradley 1996Fibromyalgia=21, Control=10

Russell et al, Arthritis Rheum 1994;37:1593-1601; Russell et al. In: Russell IJ, ed. Myopain 95: Abstracts from the 3rd
World Congress on Myofascial Pain and Fibromyalgia; Bradley et al, Arthritis Rheum 1996;suppl 9:212 Abst 1109

Pathogenesis of fibromyalgia:
Other neurotransmitters
Several bioamines have been linked to the pain

of fibromyalgia

Higher glutamate levels have been detected in

patients with fibromyalgia

Low serotonin and norepinephrine levels have been

observed in fibromyalgia patients

Evidence indicated that reduced spinal

norepinephrine may cause chronic hyperalgesia

Russell et al, Arthritis Rheum 1994;37:1593-1601; Russell et al. In: Russell, ed. Myopain 95: Abstracts from the 3rd World Congress on Myofascial Pain and
Fibromyalgia. San Antonio, Tex; July 30-August 3, 1995; Bradley, et al, Arthritis Rheum 1996;suppl 9:212 Abst 1109; Mease, J Rheumatol 2005;32:6-21

SE Asia FACTS Results

Dr Henry Lu, DABPN, DPBPM
Head, Makati Pain Control Clinic, Makati Medical Center
Head, Pain Management Center, St Lukes Medical Center Global City
Manila, Philippines

SE Asia FACTS Results

(Singapore, Indonesia, Malaysia, Thailand and Philipinnes)
Hasil :
1.

Pasien Fibromyalgia (FM) datang ke dokter terlambat

rata-rata setelah 3,3 15,4 bulan setelah menderita
FM

2.

Kebanyakan penderita mengobati sendiri

3.

Kebanyakan dokter, baik umum maupun spesialis

menyatakan belum cukup menerima training FM

Importance of diagnosis
Establishing an accurate diagnosis is an essential
component of successful management of fibromyalgia1
Data show that a diagnosis of fibromyalgia significantly
improves health satisfaction and results in fewer
symptoms by 3 years after diagnosis2
Diagnosis reduces healthcare costs3

1. Goldenberg DL, et al. JAMA 2004;292:2388-2395. 2. White KP, et al. Arthritis Rheum 2002;47:260-265.
3. Berger A, et al. Int J Clin Prac 2007;61:1498-1508.

Clinical features of fibromyalgia

WIDESPREAD PAIN
Chronic, widespread pain is the
defining feature of FM
Patient descriptors of pain include:
aching, exhausting, nagging, and
hurting

MOOD DISORDERS/
COGNITIVE DIFFICULTIES
Anxiety and depressive disorders are
common comorbidities
Significant cognitive problems in working
memory, free recall, and verbal fluency
(fibro fog)

SLEEP DISTURBANCES
TENDERNESS/STIFFNESS
Presence of tender points
Most patients also have tenderness to
pressure, heat, cold, and electrical pain
Morning stiffness is a common
characteristic of FM

Characterized by nonrestorative sleep and

increased awakenings
Abnormalities in the continuity of sleep
and sleep architecture
Reduced slow-wave sleep
Abnormal alpha wave intrusion in nonREM sleep

FATIGUE
Fatigue is a common
characteristic of FM

REM = rapid eye movement

Harding. Am J Med Sci. 1998;315:367-376; Leavitt et al. Arthritis Rheum. 1986;29:775-781; Roizenblatt et al. Arthritis Rheum. 2001;44:222-230; Weir et al.
J Clin Rheumatology. 2006;12:124-128; Wolfe et al. Arthritis Rheum. 1990:33:160-172; Wolfe et al. Arthritis Rheum. 1995;38:19-28.

American College of Rheumatology (ACR) criteria

for fibromyalgia

ACR criteria
History of chronic widespread pain
3 months
Patients must exhibit 11 of 18 tender
points
Pain in 4 quadrants and axial skeleton

Widespread pain was found in 97% of

patients with FM, compared with 70% in
controls

FM can be identified from among other

rheumatologic conditions with use of
ACR criteria

Originally developed as classification

for research purposes
Criteria need further refinement as
knowledge about FM evolves
Now commonly used to help diagnose
FM in clinical practice

ACR criteria are both

sensitive (88.4%) and specific (81.1%)
Wolfe et al. Arthritis Rheum. 1990:33:160-172.

New approach ACR-2010

Frederick Wolfe, Muhammad B. Yunus, Don L.
Goldenberg, I. Jon Russell

Wolfe F et al. Arthritis Rheum 1990;33:160-172.

Wolfe F et al.. Arthritis Care & Research Vol. 62, No. 5, May 2010, pp 600610

Rationale behind the new criteria

1990

2010

Tender point count was rarely

performed / Incorrectly in primary care
Other symptoms not considered by
ACR 1990 (fatigue, cognitive, somatic)

Tender point count ; improvement of

worsening: fail to satisfy the ACR 1990

Lets keep it simple!

To develop simple,
practical criteria for
clinical diagnosis of
fibromyalgia that are
suitable for use in primary
and specialty care and
that do not require a
tender point examination,
and to provide a severity
scale for characteristic
fibromyalgia symptoms.

Wolfe F et al.. Arthritis Care & Research Vol. 62, No. 5, May 2010, pp 600610

Diagnosis of fibromyalgia using the

Widespread Pain Index (WPI)
Note the number of areas in which the patient has had pain
over the last week. Score will be between 0 and 19.

To be used in conjunction with the Symptom Severity (SS)

scale

Upper extremity

Lower extremity

Front

Back

Shoulder girdle, left

Shoulder girdle, right
Upper arm, left
Upper arm, right
Lower arm, left
Lower arm, right

Hip (buttock, trochanter), left

Hip (buttock, trochanter, right)
Upper leg, left
Upper leg, right
Lower leg, left
Lower leg, right

Jaw, left
Upper back
Jaw, right Lower back
Chest
Neck
Abdomen

Wolfe et al. Arthritis Care Res 2010;62:600-610

SS Scale Score

Fatigue

Waking unrefreshed

Cognitive symptoms

For the each of the symptoms above, indicate the level of severity
over the past week using the following scale :
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

SS Scale Score
Considering somatic symptoms in general, indicate whether
the patient has :
0 = No symptoms
1 = Few symptoms
2 = A moderate number of symptomsmoderate level
3 = A great deal of symptoms
The SS Scale Score is the sum of the severity of the 3 symptoms
(fatigue, waking unrefreshed, cognitive symptoms)
plus the extent (severity) of somatic symptoms in general.
The final score is between 0 and 12

Somatic symptoms that might be

considered in reaching a diagnosis of
fibromyalgia
Muscle pain/weakness
Fatigue/tiredness
Cognitive problems
Headache
Abdominal pain/cramps
Numbness/tingling
Dizziness
Insomnia
Depression
Constipation
Nausea
Nervousness
Chest pain

Fever
Diarrhoea
Dry mouth
Itching
Wheezing
Raynauds phenomenon
Hives/welts
Ringing in ears
Vomiting
Heartburn
Oral ulcers
Seizures
Dry eyes

Loss of appetite
Rash
Sun sensitivity
Hearing difficulties
Easily bruised
Hair loss
Frequent urination
Painful urination
Bladder spasms
Loss of taste
Change in taste
Blurred vision
Shortness of breath
Wolfe et al. Arthritis Care Res 2010;62:600-610

Summary of ACR 2010 criteria

WPI 7 AND SS 5
OR
WPI 36 AND SS 9

This case definition of fibromyalgia correctly classifies

88% of cases classified by existing ACR 1990 classification

criteria, but does not require a tender point examination

Wolfe et al. Arthritis Care Res 2010;62:600-610

Multidisciplinary approach to
management
Strike a balance between pharmacological and nonpharmacological approaches

Initial symptom of pain, fatigue, etc

Disordered sensory processing
Neuroendocrine disturbances

Functional consequences of symptoms

Distress
Decreased activity
Isolation
Poor sleep
Increased appetite
Maladaptive illness behaviors

Dadabhoy D, Clauw DJ. Nat Clin Pract Rheumatol 2006;2:364-372.

Pharmacological therapies to
improve symptoms

Nonpharmacological therapies
to address dysfunction

Management of fibromyalgia:
Recommended treatment approach
Multidisciplinary therapy individualized to patients symptoms and
presentation is recommended
A combination of nonpharmacological and pharmacological
therapies may benefit most patients

Nonpharmacological

Pharmacological

Aerobic exercise
Cognitive behavioral therapy
Patient education
Strength training
Acupuncture*
Biofeedback*
Balneotherapy*
Hypnotherapy*

Analgesics*
Analgesic antiepileptics
Antidepressants
Other

*Limited evidence for efficacy exists

Mease P. J Rheumatol 2005;32:6-21; Carville et al, [published online ahead of print July 20, 2007] Ann Rheum Dis Doi:10.1136/ard.2007.071522; Goldenberg et
al, JAMA 2004;292:2388-2395; Clauw et al, Best Pract Res Clin Rheumatol 2003;17:685-701; Arnold et al, Arthritis Rheum 2007;56:1336-1344

Treatments used by primary care

physicians
Amitriptyline
Milnacipran
Fluoxetine
Nortriptyline

Medications Approved by FDA

to Treat Fibromyalgia:

Pregabalin
Tramadol
Moclobemide
Cyclobenzaprine

Lyrica (pregabalin)
Cymbalta (duloxetine)
Savella (milnacipran)

Duloxetine
Zolpidem

Garcia-Campayo et al. Arthritis Res Ther 2008;10:1-15.

SNRI = selective norepinephrine reuptake inhibitor.
Please see Full Prescribing Information and Medication Guide available at at this presentation.
Cymbalta, SavellaTM, and LYRICA are the trademarks of Lilly LLC, Forest Pharmaceuticals Inc, and Pfizer Inc, respectively.

Pregabalin:
Mechanism of action
and clinical data

Please see full prescribing information at this presentation.

Pregabalin is efficacious and safe for the

treatment of pain associated with fibromyalgia
Mean pain score at endpoint

6
5.8

5.7

5.6
5.4

5.26*

5.2

5.23*
5.04

5
4.8
4.0
4.4
Placebo
n=748
SD not stated
_ 0.05 vs placebo; p <_ 0.01 vs placebo
*p <

Adapted from Mease et al, J Rheum 2008;35:502-14

Pregabalin
300 mg/day

Pregabalin
450 mg/day

Pregabalin
600 mg/day

Therapeutic Actions of Ca-v 2- Drugs

Lleucine

Functional
Ca-v
channels
(via 2/4A)

Substanc
eP
NK1
receptor
IKK/IKK
IKK/NF-KB

Nucleus
NFNF-KB KB/p65/p50

Taylor,
Modifikasi
2009 Meliala, 2009

IKB/p65/p5
0

Gene
transcription
(COX2, IL6)

Pregabalin 14-week fixed-dose FM

trial: Significant improvement in pain
LS mean change from baseline

IMPROVEMENT

Placebo (n=184)
Pregabalin 300 mg (n=183)
Pregabalin 450 mg (n=190)
Pregabalin 600 mg (n=188)*

-1

-2

10

11

13

14

EP

-3
0

12

Week
P<0.01; P.0125.
*600 mg/day of pregabalin is not an approved dose for FM.
End point mean pain score based on modified baseline observation carried forward approach (mBOCF).

Arnold
et al.
APSlower
2007;
Datarepresents
on file. Pfizer
Inc, New York, NY.
Baseline mean = 6.7 (moderate to severe pain); P valuebased LS means using MMRM ANCOVA.
Scored
0-10,
score
improvement.

Proportion of Patients Who

Did not Lose Therapeutic Effect

Pregabalin 6-month durability FM trial: Primary

efficacy analysis time to loss of therapeutic
response (LTR)
Time To Loss Of
Therapeutic Response

Percent of Patients Maintaining

Response Over Time

1.0
0.9
0.8

P<.001 vs placebo

0.7
0.6
0.5
0.4
0.3
0.2

Pregabalin (n=279)

0.1

Placebo (n=287)

Time to
50% of
patients
with LTR

Placebo
(N=287)

Pregabalin
all doses
(N=279)

19 days

Not reached

0
0

30
Day 19

60

90

120

150

180

Days

At no time during the trial did more than 50% of pregabalin treated patients lose their therapeutic response
By day 19, >50% of placebo patients had discontinued therapy due to LTR
Incidence of LTR: 32% pregabalin and 61% placebo.

Crofford et al. APS, 2007; Data on file. Pfizer Inc, New York, NY.

Most frequent adverse reactions* by dose in

controlled trials of pregabalin in FM (% pts)

600 mg/d of pregabalin is not an approved dose for FM

Pregabalin dose (mg/d)

Placebo
(n=505)

150
(n=132)

300
(n=502)

450
(n=505)

600
(n=378)

All Doses
(n=1517)

Dizziness

23

31

43

45

38

Somnolence

13

18

22

22

20

Weight gain

10

10

14

11

Blurred vision

12

Dry mouth

Constipation

10

Euphoric mood

Peripheral edema

Balance disorder

Disturbed attention

Increased appetite

Adverse reaction

*Those reported in 5% of all pregabalin-treated patients and twice the rate of placebo.
Assessment of safety and tolerability was based on the 3 fixed-dose trials in FM.

Lyrica (pregabalin) Capsules Cv [package insert]. New York, NY: Pfizer Inc; 2007.

Conclusions
Fibromyalgia is a debilitating chronic widespread pain condition
with increased pain sensitivitythe extreme end of a spectrum of
abnormal pain perception / processing and has a negative
impact on patients' quality of life
More understanding and awareness of fibromyalgia is needed for
early detection and treatment
Early and accurate diagnosis helps patients with fibromyalgia and
may reduce healthcare costs
Fibromyalgia management may be improved using a
multidisciplinary approach
Pregabalin is efficacious and well-tolerated in the treatment of
fibromyalgia pain

SALAM
SAMPAI JUMPA LAGI