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)  Central (non-nociceptive)
± Primarily due to a central ± Primarily due to inflammation disturbance in pain processing or damage in periphery ± Tricyclic responsive ± NSAID, opioid responsive ± Behavioral factors more prominent ± Behavioral factors minor ± Examples ± Examples  Fibromyalgia  OA  Irritable bowel syndrome  Acute pain models (e.g.  Tension and migraine headache third molar, post-surgery)  Interstitial cystitis /  RA Mixed vulvodynia, non-cardiac  Cancer pain chest pain / etc.  Neuropathic

Effect Sizes of Various Treatments in Fibromyalgia - I
(Rossy et. Al. Ann Behav Med 1999)

Pharmacologic

Exercise

CBT

Symptoms Psychological status Functional status

.49 (n=35)

.56 (n=8)

.63 (n=6)

.52 (n=16)

.38 (n=5)

.60 (n=5)

.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 Psychological status Functional status

.49 (n=12)

.47 (n=8)

.06 (n=3)

.22 (n=4)

.26 (n=3)

.49 (n=1)

.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 as bad as it could be .

Patients only use a portion of scale. 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 . no linearity to scale  VAS only captures a single dimension of pain experience ± Multidimensional scales e. and different portions of the scales. worst pain imaginable) ± Scaling problems . validity standpoint ± Anchor is something that patient may have never experienced (i.g.Problems with Current Methods of Pain Measurement  VAS not a good measure from reliability.e. McGill Pain Questionnaire   Problems with retrospective report of any symptom.

and so that each interval in scale represents the same magnitude of change 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 EXTREMELY INTENSE VERY INTENSE INTENSE STRONG SLIGHTLY INTENSE BARELY STRONG MODERATE MILD VERY MILD WEAK VERY WEAK FAINT NO PAIN SENSATION .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.

yet actual compliance was 11% On 32% of days binder was not opened. al. recorded 89% compliance with entries within 30 minute window. asking them to record both paper and electronic entries of pain levels Unbeknownst to subjects. over 21 days. yet compliance recordings for those days averaged 90% .Patient Compliance with Paper and Pencil Diaries     Stone et. (BMJ 2002) performed study of 80 chronic pain pts. there was microchip imbedded into paper diaries that could tell when diary was opened Pts.

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 Calc Week Weekly Pain Raw Data Linear (Calc Week) Linear (Weekly Pain) 10 9 8 7 6 5 4 3 2 1 0 0 2 4 6 ee 8 10 12 core 14 .

Conclusions I ± Various Pain Measures  Less frequent sampling of pain leads to increased baseline scores (Cypress Phase II data. n=125) RP Daily 12.7 2 7 Weekly/ Paper 15.4 14 1 Weekly 12.9 50 0 .0 1 7/30 Baseline score (0-20) Assessments used Recall interval (days) 11.

Units 19 co 17 Offsets 2. Units 15 13 11 9 7 5 0 2 4 6 t dy 8 10 12 14 ra c e ly a in .Compari on of RP to eekly Diary Pain ampling Measures R andom ro m p t a in or : - 4.

all patents) 2.3 Weekly/ Paper 11.0 2.4 3.7 .4 2.3 Endpoint score 9.9 Change from baseline (clinical improvement. BUT not to the same degree as what is seen at baseline RP Daily 10.0 Weekly 10.Conclusions II ± Various Pain Measures  Less frequent sampling of pain leads to increased endpoint scores.

. with an average increase of over 4 units (0-20 scale) at the beginning of the trial. We speculate that elevated initial scores on the paper clinic assessments may relate to anxiety.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. initial lack of familiarity with the assessment scales. and 2 units at the end. and/or demand characteristics. this observation merits further explanation and consideration. As an artificially elevated baseline value would affect interpretation of all later results during an interventional trial.

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 .

g. tender points) Psychobehavioral factors  General ³distress´  Cognitive factors  Psychiatric comorbidities  Maladaptive illness behaviors  Secondary gain issues Neurobiological factors  Abnormal sensory processing  Autonomic dysfunction  HPA dysfunction  ? Peripheral factors .The Neurobiological / Psychobehavioral Continuum Population Primary Care Tertiary Care Definition factors (e..

Interaction between Symptoms and Function in FM ³STRESS´ Psychological and Behavioral Consequences Symptoms ‡ Decreased activity ‡ Poor sleep ‡ Increased distress GENES ENVIRONMENT ‡ Maladaptive illness behaviors .

vacuum a rug. stiffness. tense/anxious. make beds. drive a car ± Seven VAS measuring how much pain interfered with job. tiredness. visit friends and relatives. do yard work. depressed . prepare meals. wash dishes by hand. walk several blocks. do laundry. restedness upon awakening. pain.Potential Functional Status Measures in FM  Fibromyalgia Impact Questionnaire (FIQ) ± Able to: do shopping.

0 2. .08 Mean = 35.0 N = 80. Dev = 10.5 10.0 17. 5 7.0 22.5 37 .00 .5 25.5 17 .5 15.5 22 .Problems with ³Floor Effect´ for FIQ FIQ_PF8 20 PCS_8 20 Lower number = higher function 10 Higher number = higher function 10 Frequency Frequency Std.5 57 .5 27 .0 12.1 0 0.5 20.71 Mean = 9.0 27.5 52 5 7.5 0 N = 125. FIQ_PF8 PCS_8 Results of FIQ and SF-36 PCS at end of milnacipran Phase II trial .5 5.0 7.5 30.5 12 5 2. Dev = 7.5 32 .00 Std.

general health and vitality) Health Assessment Questionnaire Fibromyalgia HAQ .Potential Functional Status Measures in FM    SF-36 ± Physical Component Summary (PCS) Score (physical functioning. role limitations due to physical problems. bodily pain.

Andre Barkhuizen 4. OR. MA.6VA Cooperative Trials Coordinating Center. Indianapolis.3VAMC Boston. and the CSP #470 Study Group 1University of Michigan.9VA Research and Development. West Haven. Washington. IN. DC. White River.2Walter Reed Army Medical Center. Ann Arbor. DC . David A Williams 1. Boston. Daniel J Clauw 1. Washington. Lew Kazis 8. John R Feussner 9. Charles C Engel 2. Bedford. James S Skinner 5. Peter Guarino 6. Portland.7White River Junction VA. VT..5Indiana University. Peter Peduzzi 6. MA.8VAMC Bedford. MI. Thomas Taylor 7.Effectiveness of Aerobic Exercise and Cognitive Behavioral Therapy in Chronic Multisymptom Illnesses: Results from CSP #470 Sam Donta 3. CT.4Oregon Health Sciences University.

over 700. and gastrointestinal disturbances . within months of returning from the war many soldiers were complaining of illnesses The primary symptoms seen were joint and muscle pain.S. troops were deployed to the Persian Gulf Although there were very few combat casualties.S.000 U. difficulties with memory. headaches. rash.The U. fatigue. Gulf War Experience .I    In 1990 and 1991.

but in fact have been seen in veterans of every war that the U.The U. chronic fatigue syndrome.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.S.S. and go by names such as fibromyalgia. Gulf War Experience . has ever been involved in ± No specific exposures (except a single study implicating vaccines) have been shown to lead to this constellation of symptoms . somatoform disorders ± These symptoms are indeed more common in Gulf War veterans.

Chronic Multi-symptom Illnesses (CMI)  Term coined by the CDC in 1999 to describe multiple somatic symptoms in Gulf War veterans (Fukuda et. Doebbling et. JAMA 1999) This study and subsequent studies in the general population using factor analytic techniques (e. 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 . al. al..g.

silicone breast implants.g. fatigue and 4/8 ³minor criteria´ SOMATOFORM DISORDERS 4% of population. Gulf War Illnesses.4% of population.Overlap between Fibromyalgia and Other ³Systemic´ Syndromes: Chronic Multi-symptom Illnesses FIBROMYALGIA 2 .no organic findings EXPOSURE SYNDROMES e.symptoms in multiple organ systems in response to multiple substances CHRONIC FATIGUE SYNDROME 1% of population. defined by widespread pain and tenderness MULTIPLE CHEMICAL SENSITIVITY . sick building syndrome . multiple unexplained symptoms .

last for more than six months. and be present at the time of screening. . 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.Inclusion criteria  To be eligible veterans had have been deployed to the Gulf War between August 1990 and August 1991.

2) exercise alone. Both CBT and exercise were delivered in groups of three to eight participants. Exercise prescriptions focusing on low impact exercise were individualized for each participant after they performed a submaximal cycle ergometer exercise test at baseline. or 4) usual care. . CBT Treatment sessions were 60-90 minutes long and met weekly for 12 weeks.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. 3) CBT + exercise. 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.

6 and 12 months. 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) .Outcome measures    Treatments were given for three months using standard protocols and participants were evaluated at baseline. 3. 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.

7 years Based on the Prime MD: ± 45% percent of veterans had either a major depressive disorder or dysthymia. .7 81% presented with all three cardinal symptoms of GWVI at the time of screening The mean duration of symptoms was 6. ± 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.Results ± Demographics of Participants      85% male Mean age 40.

Ware.7 42. 1995 .C.195) Kazis.7 Healthy Normals (n=2.6 43. Kosinski.3 33. Keller. (1999.329) Hypertension (n=816) Type II Diabetes (n=123) Myocardial Infarction (n=50) Congestive Heart Failure (n=69) Vets GWI (n=1092) Vets FMS (n=4.7 38. P.Physical Component Summary (PCS) of the SF-36 Mean Score 50.1 45.7 28.).

and with exercise plus CBT compared to usual care.4% for CBT 18. distress.7% for exercise 18. and mental health functioning were observed with exercise alone.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. . cognitive symptoms.5% for CBT + exercise  More significant improvements in fatigue.

al.01 function and other outcomes in OA ± NSAID trials Pain walking Pain subscale Pt.67 Bolognese et.64 .Correlations between changes in outcome measures in CMI  Correlation of change in symptoms with change in PCS score (12 months to baseline) Correlations between WOMAC± Pain ± General fatigue ± Physical fatigue ± Cognitive dysfunction ± MCS .40 ..80 .71 .87 .64 .35 ..34 .42 -. global .. J Rheum 2001 .

distress and mental health functioning. pain. etc. cognitive symptoms. This and other studies suggest weaker correlations between improvements in symptoms (e. Exercise. with or without CBT.g. 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. resulted in improvement in fatigue.Conclusions      This cohort with CMI had extremely low levels of selfreport function.) and improvement in function in FM than in other rheumatic disorders . There were no additive or synergistic effects between the two treatments. fatigue.

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 .

Bethesda. M. Kop.1. Ph. Clauw. M. Daniel J. Ali Berlin2.D. Ann Arbor. MD . M. Kirsten Ambrose.S. MI Uniformed Services University of the Health Sciences.D.S. Willem J.1.How do Fibromyalgia Patients Really ³Function´? Angela Lyden.2.1 1Chronic Pain and Fatigue Research Program 2Department of Medical and Clinical Psychology University of Michigan.

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 . selfreported.Relationship between symptoms.

although not specific Results highly correlated with actual physical activity in most settings. including modest correlation with activity in RA . sensor integrates information to produce an electrical current of varying magnitude Greater the degree = higher voltage Sensitive device.Actigraphy       Designed for long-term monitoring of gross motor activity Omnidirectional wristwatch-like device Accelerometer monitors the occurrence and degree of motion.

. Ben .Actiwatch®-Scor Mini-Mitter Co. OR . Inc.

reading Got up Walking . reading Getting ready Office work-desk Sleeping Swimming Office work-desk Couch sitting.Actogram I Preparing dinner Running Walking In bed.

Participants rated symptoms ("pain".9) not engaging in high-exercise activities.Methods / Subjects   Thirty patients with FM (mean age=41. . "tired". "stressed") on 10-point scales 5 times/day based on actigraphdriven alerts. Actigraphs were worn for 5 consecutive days and four consecutive nights.5) were compared with 29 control participants (mean age=38. Activity levels were sampled over 5 min epochs.

Activity  Average daytime and nighttime activity levels were nearly identical in the patient and the control groups (p=ns).Results . Daytime Patients Controls 1456s429 1445s556 Nighttime 147s156 152s107 PCS 36 56 .

p=0.Peak Activity   Peak activity was significantly lower in the patient group relative to the control group (p=0.  7870 s 3223 vs. 12178 s 7862 activity units Variability of peak activity was significantly different between groups  Levene¶s test on SDs.008).001 .

Error Bars=SEM ¨ ¨ § ¦ ¡¡¡¥¤ ¡¡¡¡¤ ¡¡¡£ ¡¡¡¢ ¡¡¡   U n it s ( A c t iv it y ) n in g .05.M o r n in g A ft rn o o n Ev *p<0.Average and Diurnal Peak Activity Levels of Fibromyalgia Compared to Controls ¡¡¡ ¤   * C o n tr o l F ib r o m y lg i * * * o r n in g M i .

Actogram II FM patient Days of higher activity followed by days of less activity Control Higher peak activity. less sporadic .

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. fatigue and stress were higher in the patient group relative to the control group.Relationship of Activity to Symptoms   Peak and average ratings of pain.

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 .

allow use of > making IMPROVEMENT measure because of floor effect of FIQ) DEFINE RESPONDER BY BOTH 1) MCID IMPROVEMENT IN PAIN This is AND/OR CONSIDER ACR-20 TYPE OF COMPOSITE a legitimate 2) IMPROVEMENT IN unmet therapeutic need (RA AND syndrome with a large PT. diseases with effective therapies). Depression precedents) THAT MIGHT WORK EXTREMELY WELL IN A SINGLE SYMPTOM USE 2003 RCT STANDARDS (ITT. and 3) ³function´ MUST HAVE VERYthat we are INTERPRETATIONperson´ worse while Must make sure LIBERAL not making ³whole OF ³FUNCTION´ AND LOW EXPECTATIONS FOR their pain better (i. GLOBAL or OA 30 years ago).e. IBS.Options for Primary Outcome in FM Trials Where should we set the bar? Use standards being proposed for analgesics (drawn from experiences in nociceptive pain disorders. 2) global well being. thus improvement in a single defining domain is (RECOGNIZE PROBLEMS WITH THIS PRECEDENT VIS-A-VIS DRUGS adequate (Migraine. that propose that there is improvement in 1) pain. Responder) DOMAIN) PAIN Primary Outcome .

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