outcome measures in fibromyalgia daniel j. clauw, md professor of medicine, division of rheumatology...

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.

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



Functional status– Subjective– Objective - Activity monitoring




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

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)

outcome measures in fibromyalgia daniel j. clauw, md professor of medicine, division of rheumatology...

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