Post on 22-Dec-2015
Outcome Measures in Fibromyalgia
Daniel J. Clauw, MD
Professor of Medicine, Division of Rheumatology
Director, Chronic Pain and Fatigue Research Program
University of Michigan Medical Center
Chronic Pain – Defined by Mechanisms
Peripheral (nociceptive)– Primarily due to inflammation
or damage in periphery– NSAID, opioid responsive– Behavioral factors minor– Examples
OA Acute pain models (e.g.
third molar, post-surgery) RA Cancer pain
Central (non-nociceptive)– Primarily due to a central
disturbance in pain processing– Tricyclic responsive– Behavioral factors more
prominent – Examples
Fibromyalgia Irritable bowel syndrome Tension and migraine
headache Interstitial cystitis /
vulvodynia, non-cardiac chest pain / etc.
Mixed Neuropathic
Effect Sizes of Various Treatments in Fibromyalgia - I
(Rossy et. Al. Ann Behav Med 1999)
Pharmacologic Exercise CBT
Symptoms .49 (n=35) .56 (n=8) .63 (n=6)
Psychological status .52 (n=16) .38 (n=5) .60 (n=5)
Functional status .19 (n=6) .29 (n=3) .38 (n=3)
Effect Sizes of Various Treatments in Fibromyalgia - II
(Rossy et. Al. Ann Behav Med 1999)
Antidepressants Muscle relaxants NSAIDs
Symptoms .49 (n=12) .47 (n=8) .06 (n=3)
Psychological status .22 (n=4) .26 (n=3) .49 (n=1)
Functional status .15 (n=4) .24 (n=1) -.25 (n=1)
Effect Sizes of Various Treatments in Fibromyalgia – III
(Arnold et. al. Psychosomatics 2000)
Pooled effects sizes of nine trials of tricyclics– Sleep .69– Physician global .64– Pain .57– Fatigue .52– Patient global .50– Tenderness .36
Potential Outcome Measures in FM
Pain– Type of scale– Measured how?
Functional status– Subjective– Activity monitoring
Patient global improvement Other symptoms
– Fatigue– Sleep– Cognitive symptoms
Process / surrogate outcome measures– Evoked pain– Functional imaging
Visual Analog Scale
No Pain
Pain asbad as itcould be
Problems with Current Methods of Pain Measurement
VAS not a good measure from reliability, validity standpoint– Anchor is something that patient may have never experienced (i.e. worst
pain imaginable)– Scaling problems - Patients only use a portion of scale, and different
portions of the scales, no linearity to scale VAS only captures a single dimension of pain experience
– Multidimensional scales e.g. McGill Pain Questionnaire Problems with retrospective report of any symptom, and lack of
accounting for variability in pain over time Miss other important domains of pain that may be as important
to outcomes as intensity of pain
Better scales
Add verbal anchors so that choosing a point in scale is not an exercise in imagination and fractionation
Make scale logarithmic so that a wider range can be used, and so that each interval in scale represents the same magnitude of change
20
19
1817161514
12
10
13
11
EXTREMELY INTENSE
MODERATE
SLIGHTLY INTENSE
BARELY STRONG
VERY INTENSE
INTENSE
STRONG
9876543
12
0
MILD
FAINT
VERY WEAK
VERY MILD
WEAK
NO PAIN SENSATION
Patient Compliance with Paper and Pencil Diaries
Stone et. al. (BMJ 2002) performed study of 80 chronic pain pts. over 21 days, asking them to record both paper and electronic entries of pain levels
Unbeknownst to subjects, there was microchip imbedded into paper diaries that could tell when diary was opened
Pts. recorded 89% compliance with entries within 30 minute window, yet actual compliance was 11%
On 32% of days binder was not opened, yet compliance recordings for those days averaged 90%
Patient Experience Diary
Prompts subjects at any pre-determined interval to answer any number of questions
When device is placed in cradle each night modem downloads information to central location
InVivo Data
Example of data from single fibromyalgia subject
EW
0123456789
10
0 2 4 6 8 10 12 14
Week
Sc
ore
Calc Week
Weekly Pain
Raw Data
Linear (Calc Week)
Linear (Weekly Pain)
Conclusions I – Various Pain Measures
Less frequent sampling of pain leads to increased baseline scores (Cypress Phase II data; n=125)
11.9 12.4 12.7 15.0Baseline score (0-20)
Assessments used 50 14 2 1
Recall interval (days) 0 1 7 7/30
RP Daily WeeklyWeekly/Paper
Random Prompt Pain Scores: 09-015
5
7
9
11
13
15
17
19
0 2 4 6 8 10 12 14
Study Week
Gra
cely
Pain
Sco
re
Comparison of RP to Weekly Diary Pain Sampling Measures
4.0 Units
2.1 Units
Offsets
Conclusions II – Various Pain Measures
Less frequent sampling of pain leads to increased endpoint scores, BUT not to the same degree as what is seen at baseline
Change from baseline(clinical improvement,all patents)
2.0 2.4 2.4 3.7
9.9 10.0 10.3 11.3Endpoint score
RP Daily WeeklyWeekly/Paper
Summary
Random prompt pain is extremely variable in fibromyalgia patients, much moreso than paper values
The clinic (paper) weekly and monthly pain values were higher than random prompt values from the same days and weeks, with an average increase of over 4 units (0-20 scale) at the beginning of the trial, and 2 units at the end.
We speculate that elevated initial scores on the paper clinic assessments may relate to anxiety, initial lack of familiarity with the assessment scales, and/or demand characteristics.
As an artificially elevated baseline value would affect interpretation of all later results during an interventional trial, this observation merits further explanation and consideration.
Potential Outcome Measures in FM
Pain– Type of scale– Measured how?
Functional status– Subjective– Activity monitoring
Patient global improvement Other symptoms
– Fatigue– Sleep– Cognitive symptoms
Process / surrogate outcome measures– Evoked pain– Functional imaging
The Neurobiological / Psychobehavioral Continuum
Neurobiological factors Abnormal sensory
processing Autonomic 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)
Symptoms
Psychological and Behavioral
Consequences
• Decreased activity
• Poor sleep
• Increased distress
• Maladaptive illness behaviors
Interaction between Symptoms and Function in FM
“STRESS”
ENVIRONMENT
GENES
Potential Functional Status Measures in FM
Fibromyalgia Impact Questionnaire (FIQ)– Able to: do shopping, do laundry, prepare
meals, wash dishes by hand, vacuum a rug, make beds, walk several blocks, visit friends and relatives, do yard work, drive a car
– Seven VAS measuring how much pain interfered with job, pain, tiredness, restedness upon awakening, stiffness, tense/anxious, depressed
Problems with “Floor Effect” for FIQ
FIQ_PF8
30.0
27.5
25.0
22.5
20.0
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0.0
FIQ_PF8
Fre
qu
en
cy
20
10
0
Std. Dev = 7.71
Mean = 9.1
N = 80.00
PCS_8
PCS_8
Fre
quen
cy
20
10
0
Std. Dev = 10.08
Mean = 35.5
N = 125.00
Results of FIQ and SF-36 PCS at end of milnacipran Phase II trial
Lower number = higher function
Higher number = higher function
Potential Functional Status Measures in FM
SF-36
– Physical Component Summary (PCS) Score (physical functioning, role limitations due to physical problems, bodily pain, general health and vitality)
Health Assessment Questionnaire Fibromyalgia HAQ
Effectiveness of Aerobic Exercise and Cognitive Behavioral Therapy in Chronic
Multisymptom Illnesses:
Results from CSP #470 Sam Donta 3, Daniel J Clauw 1, Charles C Engel 2,, Andre Barkhuizen 4, James S Skinner 5, Peter Peduzzi 6, Peter
Guarino 6, David A Williams 1, Thomas Taylor 7, Lew Kazis 8, John R Feussner 9, and the CSP #470 Study Group
1University of Michigan, Ann Arbor, MI;2Walter Reed Army Medical Center, Washington, DC;3VAMC Boston, Boston,
MA;4Oregon Health Sciences University, Portland, OR;5Indiana University, Indianapolis, IN;6VA Cooperative Trials Coordinating Center, West Haven, CT;7White River Junction VA, White River, VT;8VAMC Bedford, Bedford, MA;9VA Research and Development, Washington, DC
The U.S. Gulf War Experience - I
In 1990 and 1991, over 700,000 U.S. troops were deployed to the Persian Gulf
Although there were very few combat casualties, within months of returning from the war many soldiers were complaining of illnesses
The primary symptoms seen were joint and muscle pain, headaches, fatigue, difficulties with memory, rash, and gastrointestinal disturbances
The U.S. Gulf War Experience - II
After all of this research, several facts are now clear:– The symptoms that Gulf War veterans suffer from
represent the same clusters of symptoms that occur in the general population, and go by names such as fibromyalgia, chronic fatigue syndrome, somatoform disorders
– These symptoms are indeed more common in Gulf War veterans, but in fact have been seen in veterans of every war that the U.S. has ever been involved in
– No specific exposures (except a single study implicating vaccines) have been shown to lead to this constellation of symptoms
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
Overlap between Fibromyalgia and Other “Systemic” Syndromes:
Chronic Multi-symptom Illnesses
FIBROMYALGIA 2 - 4% of population; defined by widespread
pain and tenderness
EXPOSURE SYNDROMES e.g. Gulf War Illnesses, silicone breast implants, sick building syndrome
CHRONIC FATIGUE SYNDROME 1% of population; fatigue and 4/8 “minor criteria”
SOMATOFORM DISORDERS 4% of population; multiple unexplained symptoms - no organic findings
MULTIPLE CHEMICAL SENSITIVITY - symptoms in multiple organ systems in response to multiple substances
Inclusion criteria
To be eligible veterans had have been deployed to the Gulf War between August 1990 and August 1991, and to endorse > 2 of the following symptoms: – fatigue limiting usual activity – pain in > 2 body regions – neurocognitive symptoms
These symptoms had to begin after August 1990, last for more than six months, and be present at the time of screening.
Subjects / Methods
1092 veterans who satisfied the eligibility criteria and gave written informed consent were randomized to one of four treatment arms: 1) CBT alone, 2) exercise alone, 3) CBT + exercise, or 4) usual care.
Both CBT and exercise were delivered in groups of three to eight participants.
CBT Treatment sessions were 60-90 minutes long and met weekly for 12 weeks.
Exercise prescriptions focusing on low impact exercise were individualized for each participant after they performed a submaximal cycle ergometer exercise test at baseline. Veterans in the exercise group were asked to exercise once/wk in the presence of the exercise therapist, and 2 – 3X / wk independently during the 12-week treatment phase.
Outcome measures
Treatments were given for three months using standard protocols and participants were evaluated at baseline, 3, 6 and 12 months.
The primary endpoint was the proportion of participants who improved more than 7 units on the physical component summary scale of the Veterans Short Form 36-item (SF-36) Health Survey at 12 months after randomization.
Secondary outcomes were standardized measures of:– Pain (McGill Pain Questionnaire)– Fatigue (Multidimensional Fatigue Inventory)– Cognitive symptoms (Cognitive Failures Questionnaire)– Distress (Mental Health Inventory – 5 of the SF-36V)– Mental health functioning (Mental component score of the SF-36V)
Results – Demographics of Participants
85% male Mean age 40.7 81% presented with all three cardinal symptoms of GWVI
at the time of screening The mean duration of symptoms was 6.7 years Based on the Prime MD:
– 45% percent of veterans had either a major depressive disorder or dysthymia,
– 35% had an anxiety disorder – 43% had posttraumatic stress disorder
24% percent of veterans had a pending disability claim and 42% were receiving disability payments.
Physical Component Summary (PCS) of the SF-36
50.1 Healthy Normals (n=2,329)MeanScore
43.7 Type II Diabetes (n=123)
38.3 Congestive Heart Failure (n=69)
28.7 Vets FMS (n=4,195)
Hypertension (n=816)
Myocardial Infarction (n=50)
45.6
42.7
Kazis, (1999; P.C.); Ware, Kosinski, Keller, 1995
33.7 Vets GWI (n=1092)
Response to Treatment
There was a modest difference in the proportion of veterans who reported an improvement in physical function at one year among the CBT groups:– 11.5% for usual care– 11.7% for exercise– 18.4% for CBT – 18.5% for CBT + exercise
More significant improvements in fatigue, cognitive symptoms, distress, and mental health functioning were observed with exercise alone, and with exercise plus CBT compared to usual care.
Correlations between changes in outcome measures in CMI
Correlation of change in symptoms with change in PCS score (12 months to baseline)– Pain .34– General fatigue .40– Physical fatigue .42– Cognitive dysfunction -.35– MCS .01
Correlations between WOMAC-function and other outcomes in
OA – NSAID trials
Pain walking .71 - .80
Pain subscale .64 - .87
Pt. global .64 - .67
Bolognese et. al. J Rheum 2001
Conclusions
This cohort with CMI had extremely low levels of self-report function, like other cohorts with FM
CBT specifically aimed at improving physical function had only a marginally significant impact on self-reported physical function for veterans with GWVI.
Exercise, with or without CBT, resulted in improvement in fatigue, cognitive symptoms, distress and mental health functioning.
There were no additive or synergistic effects between the two treatments.
This and other studies suggest weaker correlations between improvements in symptoms (e.g. pain, fatigue, etc.) and improvement in function in FM than in other rheumatic disorders
Potential Outcome Measures in FM
Pain– Type of scale– Measured how?
Functional status– Subjective– Objective - Activity monitoring
Patient global improvement Other symptoms
– Fatigue– Sleep– Cognitive symptoms
Process / surrogate outcome measures– Evoked pain– Functional imaging
How do Fibromyalgia Patients Really “Function”?
Angela Lyden, M.S.1, Ali Berlin2, Kirsten Ambrose, M.S.1,
Willem J. Kop, Ph.D.2, Daniel J. Clauw, M.D.1
1Chronic Pain and Fatigue Research Program
University of Michigan, Ann Arbor, MI
2Department of Medical and Clinical Psychology
Uniformed Services University of the Health Sciences, Bethesda, MD
Relationship between symptoms, self-reported, and objective measures of activity
Patients with FM have amongst the lowest self-reported activity levels of any chronic illness
This parameter has been very difficult to improve in interventional studies
How is self-reported activity related to:– Objective measures of activity– Specific symptoms
Actigraphy
Designed for long-term monitoring of gross motor activity
Omnidirectional wristwatch-like device Accelerometer monitors the occurrence and degree
of motion; sensor integrates information to produce an electrical current of varying magnitude
Greater the degree = higher voltage Sensitive device, although not specific Results highly correlated with actual physical
activity in most settings, including modest correlation with activity in RA
Actiwatch®-ScoreMini-Mitter Co., Inc. Bend, OR
Actogram I
Running
Swimming
Office work-desk
Walking
Preparing dinner
Couch sitting; reading
In bed; reading
Sleeping
Got up
Getting ready
Walking
Office work-desk
Methods / Subjects
Thirty patients with FM (mean age=41.5) were compared with 29 control participants (mean age=38.9) not engaging in high-exercise activities.
Actigraphs were worn for 5 consecutive days and four consecutive nights. Activity levels were sampled over 5 min epochs. Participants rated symptoms ("pain", "tired", "stressed") on 10-point scales 5 times/day based on actigraph-driven alerts.
Results - Activity
Average daytime and nighttime activity levels were nearly identical in the patient and the control groups (p=ns).
Daytime Nighttime PCS
Patients 1456429 147156 36 Controls 1445556 152107 56
Peak activity was significantly lower in the patient group relative to the control group (p=0.008).
7870 3223 vs. 12178 7862 activity units
Variability of peak activity was significantly different between groups
Levene’s test on SDs, p=0.001
Peak Activity
Units (
Activity)
4000
6000
8000
10000
12000
14000
Morning Mid-Morning Afternoon Evening
ControlFibromyalgia
Average and Diurnal Peak Activity Levels of Fibromyalgia Compared to
Controls
*p<0.05; Error Bars=SEM
*
**
*
Actogram IIFM patient
Days of higher activity followed by days of less
activity
Control
Higher peak activity, less sporadic
Relationship of Activity to Symptoms
Peak and average ratings of pain, fatigue and stress were higher in the patient group relative to the control group, but these symptoms were not related to activity in either patient or control groups.
Actigraphy results (average or peak) were not significantly correlated with self-report function (SF-36) in either patients or controls.
Conclusions – Function in FM
FM patients rate their function as being very low This domain has been the most difficult to improve in
clinical trials Dysfunction in FM patients is fundamentally different
than dysfunction in other rheumatic diseases . . . there is less of a relationship between improvements in symptoms and improvements in function in FM
It is not clear what these self-report measures of function are actually measuring
Potential Outcome Measures in FM
Pain– Type of scale– Measured how?
Functional status– Subjective– Activity monitoring
Patient global improvement Other symptoms
– Fatigue– Sleep– Cognitive symptoms
Process / surrogate outcome measures– Evoked pain– Functional imaging
Potential Outcome Measures in FM
Pain– Type of scale– Measured how?
Functional status– Subjective– Activity monitoring
Patient global improvement Other symptoms
– Fatigue– Sleep– Cognitive symptoms
Process / surrogate outcome measures– Evoked pain– Functional imaging
Potential Outcome Measures in FM
Pain– Type of scale– Measured how?
Functional status– Subjective– Activity monitoring
Patient global improvement Other symptoms
– Fatigue– Sleep– Cognitive symptoms
Process / surrogate outcome measures– Evoked pain– Functional imaging
Potential Outcome Measures in FM
Pain– Type of scale– Measured how?
Functional status– Subjective– Activity monitoring
Patient global improvement Other symptoms
– Fatigue– Sleep– Cognitive symptoms
Process / surrogate outcome measures– Evoked pain– Functional imaging
Potential Outcome Measures in FM
Pain– Type of scale– Measured how?
Functional status– Subjective– Activity monitoring
Patient global improvement Other symptoms
– Fatigue– Sleep– Cognitive symptoms
Process / surrogate outcome measures– Evoked pain– Functional imaging
Options for Primary Outcome in FM Trials
Where should we set the bar?
This is a legitimate syndrome with a large unmet therapeutic need (RA or OA 30 years ago), thus improvement in a single defining domain is
adequate (Migraine, IBS, Depression precedents)
USE 2003 RCT STANDARDS (ITT, Responder)
PAIN Primary Outcome
Must make sure that we are not making “whole person” worse while making their pain better
DEFINE RESPONDER BY BOTH 1) MCID IMPROVEMENT IN PAIN AND 2) IMPROVEMENT IN PT. GLOBAL
Use standards being proposed for analgesics (drawn from experiences in nociceptive pain disorders, diseases with effective therapies), that propose that there is improvement in 1) pain, 2) global well being, and 3) “function”
MUST HAVE VERY LIBERAL INTERPRETATION OF “FUNCTION” AND LOW EXPECTATIONS FOR IMPROVEMENT (i.e. allow use of >
measure because of floor effect of FIQ)
AND/OR CONSIDER ACR-20 TYPE OF COMPOSITE
(RECOGNIZE PROBLEMS WITH THIS PRECEDENT VIS-A-VIS DRUGS THAT MIGHT WORK EXTREMELY WELL IN A SINGLE SYMPTOM
DOMAIN)