Transcript This Evening’s Agenda - University of Kentucky

Workshop agenda
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Welcome and Introductions
Fibromyalgia: What do we know?
Stretch break
Non-drug Treatment of Fibromyalgia
Pharmacologic Treatment of Fibromyalgia
Questions & Answers
Fibromyalgia:
What do we know?
Leslie J. Crofford, M.D.
Gloria W. Singletary Professor
Chief, Division of Rheumatology & Women’s Health
Director, Center for the Advancement
of Women’s Health
University of Kentucky
Fibromyalgia:
1990 American College of
Rheumatology Criteria
• Chronic widespread
pain in all four
quadrants of the
body and the axial
skeleton
• 11 / 18 tender points
(patient experiences
pain with 4 kg of
pressure)
Fibromyalgia Syndrome
• Symptoms
– Widespread chronic pain
– Fatigue
– Unrefreshing sleep
– Cognitive dysfunction
– Depression and anxiety
– Regional musculoskeletal pain
– Visceral pain
Overlapping Systemic
Syndromes
FIBROMYALGIA
2 - 4% of population;
defined by widespread
pain and tenderness
EXPOSURE
SYNDROMES e.g.
Gulf War Illnesses, silicone
breast implants, sick building
syndrome
MULTIPLE CHEMICAL
SENSITIVITY - symptoms in
multiple organ systems in
response to multiple substances
CHRONIC FATIGUE
SYNDROME 1% of
population; fatigue and
4/8 “minor criteria”
SOMATOFORM
DISORDERS 4% of
population; multiple
unexplained
symptoms - no
“organic” findings
Chronic Multi-symptom
Illnesses (CMI)
• Term coined by the CDC in 1999 to describe multiple somatic
symptoms in Gulf War veterans (Fukuda et. al. JAMA 1999)
• This study and subsequent studies in the general population using
factor analytic techniques (e.g., Doebbling et. al. Am J Med 2000)
identified 3 – 4 symptom factors that cluster in the populations
– Multifocal pain
– Fatigue
– Cognitive difficulties
– Psychological symptoms
• This and subsequent studies demonstrated that approximately 10 –
15% of the population suffers from a syndrome characterized by
two or more of these symptoms
Symptom Syndromes
• Overlapping syndromes
– systemic
– regional
• Epidemiological studies
• Insights into mechanisms
• Treatment
Regional or Organ-Specific
Symptoms and Syndromes
Related to CMI
Tension/migraine
headache
Affective disorders
Temporomandibular
joint syndrome
Cognitive difficulties
ENT complaints (sicca sx.,
vasomotor rhinits,
accommodation problems)
Vestibular complaints
Multiple chemical sensitivity,
“allergic” symptoms
Constitutional
Weight fluctuations
Night sweats
Weakness
Sleep disturbances
Irritable bowel
syndrome
Nondermatomal
paresthesias
Esophageal dysmotility
Neurally mediated hypotension,
mitral valve prolapse
Non-cardiac chest pain, dyspnea
due to respiratory mm.
dysfunction
Interstitial cystitis,
female urethral syndrome,
vulvar vestibulitis, vulvodynia
Many symptoms …
Many doctors
What causes fibromyalgia
and other CMI?
• Genetics
• “Triggers”
• Mechanisms
– Disordered sensory processing
– Autonomic/neuroendocrine
dysfunction
– Relationship between physiologic and
psychologic factors
What causes CMI?
• Genetics
• “Triggers”
• Mechanisms
– Disordered sensory processing
– Autonomic/neuroendocrine
dysfunction
– Relationship between physiologic and
psychologic factors
“Stressors” capable of triggering
these illnesses – supported by
case-control studies
• Infections (e.g., parvovirus, EBV, Lyme, Q
fever; not common URI)
• Physical trauma (automobile accidents)
• Psychological stress / distress
• Hormonal alterations (e.g., hypothyroidism)
• Drugs
• Vaccines
• Certain catastrophic events (war, but not
natural disasters)
FMS symptom domains
PAIN
- Generalized
- Regional
- Visceral
NON-PAIN
- Fatigue
- Cognitive Dysfunction
- Sleep Disturbance
- Depression/Anxiety
PAIN
Definition of pain
“An unpleasant sensory and emotional
experience associated with actual or
potential tissue damage or described in
terms of such damage” – International
Association for the Study of Pain, 1994
What causes fibromyalgia?
• Genetics
• “Triggers”
• Mechanisms
– Disordered sensory processing
– Autonomic/neuroendocrine
dysfunction
– Relationship between physiologic and
psychologic factors
Mechanisms of Pain
Brain
A-delta – 1st sharp
Stimulus
C fiber – 2nd
burning, throbbing
Willis 1985
Spinal cord
from Robert Bennett, MD
Mechanisms of Pain
Acute pain
Peripheral
nociceptive
input from
thermal,
chemical or
mechanical
nociceptors
Stimulus
Chronic pain
Brain
Central factors
typically
predominate
Spinal cord
from Robert Bennett, MD
Convergence onto a wide
dynamic range neuron (WDR)
Brain
Touch fiber
(myelinated)
WDR
Pain fiber
(unmyelinated)
Convergence onto a
“sensitized” WDR neuron
Allodynia
Pain
fiber
Touch
fiber
Sensory processing in CMI
A problem with the “volume control”
• Patients display a normal “detection threshold”, but an
increased sensitivity, to noxious levels of not only
pressure, but also other stimuli, e.g. heat, noise,
electrical stimulation.
• The general increase in sensory sensitivity could
theoretically be due to psychological or physiological
factors including:
– expectancy
– hypervigilance
– central changes in nociceptive processing (e.g., sensitization or
reduced descending pain inhibition)
Pressure pain
450
Fibromyalgia
Control
Pressure (pascals)
400
350
P<0.001
300
P<0.001
250
200
150
Geisser et al. Pain 2003.
Tender points
Control points
Thermal pain
53
Temperature (ºC)
52
Fibromyalgia
Control
51
P<0.05
50
49
48
P<0.01
47
46
45
44
43
42
Geisser et al. Pain 2003.
Threshold
Tolerance
Functional MRI in chronic pain
It is “all in your head”
• fMRI takes advantage of magnetic moment of
deoxygenated blood, and thus can detect
neuronal activations associated with stimuli
• Most imaging sequences take advantage of “onoff” paradigms, where the difference between
the blood flow in a “neutral” condition (e.g.
touch) and pain is imaged
• PET and fMRI have identified a number of brain
regions involved in pain processing
Functional MRI in Fibromyalgia
14
Pain Intensity
12
10
8
6
Fibromyalgia
4
Subjective Pain Control
2
Stimulus Pressure Control
0
1.5
2.5
3.5
Stimulus Intensity (kg/cm2)
4.5
SI
IPL
SII
STG, Insula, Putamen
Other fMRI findings
• Depression isn’t causing pain
• Cognitive factors, i.e. how someone
views their pain or reacts to it, are very
important
– Locus of control
– Catastrophizing
FMS pain is not “normal”
pain, but “central” pain
• Clear difference in pain threshold in research
studies comparing FMS and normal subjects
• Patients’ pain complaints confirmed by studies
using objective measures of brain activation
• Pain cannot be explained by tissue damage
• Pain does not respond well to usual pain
treatments
• Strong evidence for central factors in FMS pain
Treatment Implications for
Concept of Central Pain
• Treatments usually used for
musculoskeletal pain do not work well in
most FMS patients
• Treatments must address the problems:
– Altered pain processing in the spinal
cord
– Altered descending inhibition of pain
signals
FATIGUE
Chronic Fatigue Syndrome
• Chronic fatigue severe enough to limit daily
activity and four or more of the following
– Myalgia , Arthralgia
– Headache
– Tender nodes
– Sore throats
– Unrefreshing sleep
– Post exertional malaise
– Difficulty with concentration
What does “fatigue”
mean?
• General
– Decreased energy, need to rest, sleepiness or unrefreshing
sleep, struggle to overcome inactivity
• Physical
– Weakness, limb heaviness, post-exertional malaise
• Emotional
– Decreased motivation/interest
• Mental (cognitive)
– Diminished concentration/memory
• Functional
– Difficulty completing daily tasks
Possible causes of fatigue
in fibromyalgia
•
•
•
•
•
•
Sleep disturbance
Pain
Depression/anxiety
Medications
Deconditioning/muscle metabolism
Neurally-mediated hypotension
Fatigue clusters with
other FMS symptoms
Fatigue Pain
Sleep
Dep
Anxiety
Fatigue 1.000
0.507
0.519
0.482
0.422
Pain
0.507
1.000
0.373
0.216
0.211
Sleep
0.519
0.600
1.000
0.386
0.382
Dep
0.482
0.216
0.386
1.000
0.559
Anxiety 0.422
0.211
0.382
0.559
1.000
N=524-529. Fatigue=Multidimensional Assessment of Fatigue Global Index;
Pain=Pain VAS; Sleep=Sleep Problems Index; Dep=HADS Depression;
Anxiety=HADS Anxiety. All correlations significant at P>0.0001.
COGNITIVE
DYSFUNCTION
Cognitive Changes
Across the Lifespan
Digit Symbol
Letter Comparison
1.2
Pattern Comparison
0.8
Letter Rotation
Z-scores
Line Span
0.4
Computation Span
Reading Span
0
Benton
Rey
-0.4
Cued Recall
-0.8
Free Recall
n = 350
-1.2
20's
Shipley Vocabulary
Antonym Vocabulary
30's
40's
50's
60's
Age Groups
70's
80's
Synonym Vocabulary
Number Correct Trials
Working memory
32
30
28
26
24
22
20
18
16
14
12
10
p < .039
FM vs AMC
FM
Older
Controls
Age-Matched
Controls
Information processing
speed
Number Correct
150
p = .80
FM vs AMC
140
130
120
110
100
90
80
FM
Older
Controls
Age-Matched
Controls
Cognitive function in
fibromyalgia
• Cognitive complaints are accurate
– Working memory, “effortful” short-term memory,
vocabulary
• Unlikely to be explained on the basis of
depression or due to global brain dysfunction
– Processing speed normal
• Depression, anxiety, and sleep measures do not
correlate with cognitive performance
PSYCHOLOGICAL
DISTRESS
What causes fibromyalgia?
• Genetics
• “Triggers”
• Mechanisms
– Disordered sensory processing
– Autonomic/neuroendocrine
dysfunction
– Relationship between physiologic and
psychologic factors
Stress-response
and fibromyalgia
• Symptom onset and exacerbation during
periods of stress
• Clinical response of symptoms to therapeutic
agents that alter stress mediators
• Symptoms of FMS can be reproduced by
altering HPA axis physiology
• Evidence of HPA axis and ANS dysfunction
Circadian
Rhythm
Stress
Hypothalamus
CRH
Pituitary
ACTH
Cortisol
Adrenal
Cortex
Slow
wave sleep
Cortisol
mg/dL
20
10
0
700 1300 1900 100
Time
700
Central
Stress
Hippocampus
Amygdala
PVN - Hypothalamus
Pituitary
 Reproduction
 Slow Wave Sleep
Grooming
Neophobia
Pyramidal Cell FR
Locus Coeruleus FR
 Eating
 Immune Function
CRH
ACTH
Locus Coeruleus
Norepinephrine
Cortisol
HPA Axis
Gluconeogenesis
Lipolysis
Proteolysis
Insulin Resistance
 Inflammation
Epinephrine
SNS
Blood Pressure
Heart Rate
 Blood Sugar
 GI Blood Flow
PNS
Modulatory
Factors that influence physiologic
effects of stress …a stress is not
always the same stress
•
•
•
•
Control
Support
Predictability
Directionality
What causes fibromyalgia?
• Genetics
• “Triggers”
• Mechanisms
– Disordered sensory processing
– Autonomic/neuroendocrine
dysfunction
– Relationship between physiologic and
psychologic factors
Depression and anxiety
• Mood disturbance is a normal response to
feeling unwell and not being capable of
functioning at the desired level
• Depression is neither necessary nor sufficient for
having FMS or a related syndrome
• Some of the neurobiologic abnormalities seen in
FMS are shared with depression
• Can be a barrier to treatment
The Physiological /
Psychobehavioral Continuum
Population
Primary Care
Tertiary Care
Physiologic factors
Psychosocial factors
• Abnormal sensory
processing
• Autonomic and HPA
axis dysfunction
• Smooth muscle
dysmotility
• General “distress”
• Mood disorders (e.g.,
depression)
• Cognitions
• Maladaptive illness
behaviors
• Secondary gain
issues
Dually focused treatment
Psychological
and behavioral
consequences
TRIGGERS
BAD
GENES
Symptoms
•Decreased activity
•Poor sleep
•Increased distress
POOR
ENVIRONMENT
•Maladaptive illness
behaviors
Our advice to FM/CFS
patients:
1.
Focus on what you need to do to get better, not what caused your
illness

Look forward, not backwards
2. Look for treatments, not “cures”

We cure very few chronic medical illnesses; FM/CFS is not
likely to be one of them
3.
Find a health care provider who will work with you

Explain, don’t complain

Suggest a series of short visits each addressing specific
issues

Gently educate, with credible sources of information (i.e.
scientific articles)

Understand where they’re coming from.
4. Try exercise and CBT

People who recommend them don’t think you’re lazy
(exercise) or crazy (CBT)
Our advice to FM/CFS
patients:
5.
6.
Try tested therapies before untested
When trying any therapies (tested or untested), do
your own personal “clinical trial”
When you get worse, don’t assume it is because a
treatment has stopped working, and stop your
existing treatments, or look to add new treatments
7.


The natural history of these illnesses is to wax and wane
Look for stressors or changes in behavior that may have
made symptoms worse instead
Our advice to FM/CFS
patients
8. When a treatment improves symptoms, you
must correspondingly increase function
9. Think very carefully about disability or
litigation
•
•
Almost always is permanent
Almost always makes people worse
Our advice to FM/CFS
patients
10. There is hope!


Most individuals who are treated with existing
treatments that are know to work get better, and can
live normal lives
There is significant interest by the NIH,
pharmaceutical industry in this spectrum of illness.
The more money that is spent on studying these
illnesses, the more effective we will be at treating
them