# Presentation: 793308

## Basic Mechanisms of Pain and Non-Pain Symptoms of Fibromyalgia Syndrome:  Impact on Therapeutics

- Leslie J. Crofford, M.D.
- University of Michigan
- FDA Arthritis Drugs Advisory Committee Meeting
- June 23, 2003

## Developing Effective Treatments for Fibromyalgia Syndrome (FMS)

- Can FMS be clinically recognized and diagnosed using current ACR criteria?
- ACR criteria identify patients with predictable symptom profile
- FMS patients identified by ACR criteria may contain subsets (clinically or mechanistically defined)
- What are the critical symptom domains in these patients that must improve for an intervention to be an effective treatment for FMS?
- What mechanism(s) underlie FMS that may allow us to predict the types of treatments that may be effective?
- How best can we measure improvement in response to treatment?

## Slide 3

## Fibromyalgia Symptom Domains

- Pain
- Widespread MSK
- Regional MSK
- Visceral
- Required

- Non-Pain
- Fatigue
- Sleep disturbance
- Cognitive dysfunction
- Depression/anxiety
- Not required
- Almost universally present

## Attribution of Symptom Domains to Specific Mechanisms

- Pain
- Widespread clinical pain
- No mechanism implied
- ACR tender points
- Tender points measure a domain that incorporates both allodynia and non-pain domains (distress)1
- Is the pain of FMS “real”?
- Psychophysical testing
- Evoked potentials
- fMRI

- 1Wolfe.  Ann Rheum Dis  1997; 56:258.

## Pain in FMS

- •  Stimulus detection normal
- Altered noxious threshold (multimodality)
- Central representation of pain confirms veracity of subjective pain complaints
- Pain cannot be explained by tissue damage
- Pain generators may be common
- Implicates central factors in FMS pain

## Spinal Central Sensitization orActivity-dependent Plasticity

- Neuronal plasticity in the spinal cord modifies performance of nociceptive pathways
- Exaggerated or prolonged response to noxious inputs (hyperalgesia)
- Enabling normally innocuous inputs to activate nociceptive pathways (allodynia)
- Transcription independent and dependent mechanisms
- Mediators
- EAA, NMDA receptors
- SP and other neuropeptides, GPCR
- Kinases (e.g., PKC, many others)
- Phosphorylate ion channels and receptors resulting in neuronal hyperexcitability

## Descending Modulation

- Bi-directional (inhibitory and facilitatory) descending control
- Serotonergic and noradrenergic pathways
- Injury-induced hyperalgesia dampened by descending pathways
- Cortical and subcortical structures stimulate facilitatory pathways
- Input integrated at PAG/RVM
- Vagal afferents
- HPA axis and ANS
- Cortical (e.g. ACC, DLPC)
- RVM dynamic plasticity mediated by NMDA receptors

## Central Modulation of Pain

_**Cerebral Cortex**_
- -Goal-directed behaviors
- -Attention/distraction
- -Expectancy
- -Interaction with limbic system

_**Sub-cortical**_
- - Stress-induced analgesia

_**Midbrain & **_
_**Brain Stem**_
- Integrates signals from brain and spinal cord
- Site of opiate action
- Relay chemical signals to spinal cord
- Norepinephrine and serotonin

## Treatment Implications for Concept of Central Pain

- Treatments usually used for “normal” 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

## Attribution of Non-Pain Symptoms to Specific Mechanisms

- Non-pain symptoms form a “distress” cluster often associated with multifocal chronic pain1
- Fatigue exceptionally difficult to attribute
- Sleep disturbance
- No specific alteration described, but overlap with other conditions that share symptoms2, 3
- Cognitive dysfunction
- Evidence that cognitive complaints correlate with fMRI differences
- Depression, anxiety
- Marked increase in lifetime prevalence, associated with health-care seeking

- 1Nisenbaum et al.  Am J Epidemiol 1998; 148:72; 2Raines & Penzien.  J Psychosom Res 2003; 54:77;
-  3Roizenblatt et al Arthritis Rheum 2001; 44:222.

## 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 FMS

- Sleep disturbance
- Depression/anxiety
- Pain
- Medications
- Deconditioning/muscle metabolism
- Neurally-mediated hypotension
- Central mechanisms, e.g. cytokines

## Correlation Matrix

- 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.

## Sleep Disturbances in FMS

- Alpha-delta sleep
- First objective alteration described in FMS1
- Non-specific, not universal
- Reduced slow-wave (stage 3-4) sleep
- Non-specific, not universal
- No spectral analyses reported to examine delta power in FMS
- “Psychophysiologic” insomnia
- Altered sensitivity to environmental stimuli

- 1Moldofsky et al. Psychosom Med  1975; 37:341

## Cognitive Changes Across the Lifespan

**0**

**0.4**

**0.8**

**1.2**

**20's**

**30's**

**40's**

**50's**

**60's**

**70's**

**80's**

**Digit Symbol**

**Letter Comparison**

**Pattern Comparison**

**Letter Rotation**

**Line Span**

**Computation Span**

**Reading Span**

**Benton**

**Rey**

**Cued Recall**

**Free Recall**

**Shipley Vocabulary**

**Antonym Vocabulary**

**Synonym Vocabulary**

**Age Groups**

**Z-scores**

**n = 350**

## Information Processing Speed: FM are as fast as Age-matched controls

## Working Memory:FM perform like older adults

## Long-Term MemoryFree Recall: FM Perform like older adults

## Reuter-Lorenz, et al., Journal of Cognitive Neuroscience, 2001

- Reuter-Lorenz, et al., *Journal of Cognitive Neuroscience*, 2001

## Alphabetize Condition

- 10,000 ms

- 1,000 ms

- 3,000 ms

- 2,000 ms

- In this trial, participants would respond “YES,” because the letter, S, is in the correct alphabetical position.

## FM Patients: Alphabetizing - Maintenance

- FM’s show bilateral activation in middle frontal gyrus while alphabetizing (BA 6)
- Increased activation in the right superior parietal lobe (BA 7, 39)
- An area specialized for the processing of spatial location of objects; processing of meaning; storage of items during working memory tasks
- Midline medial frontal gyrus (BA 8) - Associated with Frontal Eye Fields; Facilitates eye movements and visual reflexes (e.g., pupil constriction/dilation)
- Overall, FM’s show more activation when alphabetizing

## FM Patients: Alphabetizing - Maintenance

- An additional region bordering the right inferior frontal gyrus and the precentral gyrus (involving BA 6, 9, and 44) was found in FMs.
- Right BA 44 is the homologue to Broca’s area in the left hemisphere
- BA 9 is thought to be involved in reasoning

## Controls: Alphabetizing - Maintenance

- The normal controls did not show more activation in any part of the brain. Only a small, nonsignificant region was identified at the posterior junction of the occipital and parietal lobes.
- Control subjects did not have to work harder to alphabetize compared to maintenance.

## Depression and Anxiety in Fibromyalgia

- Neither necessary nor sufficient for diagnosis of FM
- Higher point prevalence than in the general population
- Lifetime prevalence in a tertiary care population1
- Depression 68%
- Any anxiety disorder 35%
- Health-care seeking associated with psychiatric comorbidity

- 1Epstein et al, Psychosomatics, 1999; 2Bradley et al.  Arthritis Rheum 1996; 39:436

## Slide 26

## “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

## What is a “Healthy” HPA Axis?

- Circadian variation with high cortisol in am and low cortisol in pm
- High responsiveness to physiologic and stressful stimuli
- Sensitivity to dexamethasone suppression
- “Responsive and resilient”

## Low-Dose oCRH/Dex Suppression Protocol

- AM  PM

- AM  PM

- AM  PM

- AM  PM

- AM  PM

- AM  PM

- Saliva Collections

- Dex 0.25 mg

- Dex 0.50 mg

- GCRC for Low-Dose
- (0.3 ug/kg) oCRH

## Mean ACTH ± SEM Following Low Dose oCRH (0.3 ug/kg)  Stimulation 

- Mean ACTH ± SEM Following Low Dose oCRH (0.3 ug/kg)  Stimulation

- in FM (n=14) and Controls (n=12)

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**Time from oCRH administration (min)**

**ACTH (pmol/mL)**

**FM**

**Control**

***p *****= 0.047**

## Mean Salivary Cortisol Concentration ± SEM 

- Mean Salivary Cortisol Concentration ± SEM
- Pre & Post Graded Low-dose Dexamethasone
- Suppression in Controls & FM

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**AM**

**PM**

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**PM**

**DAY 2**

**DAY 3**

**DAY 4**

**DAY 5**

**DAY 6**

**DAY 7**

**Cortisol (mg/dL)**

**FM**

**Control**

***p *****= 0.22**

***p *****< 0.01**

***p***** = 0.03**

***p *****= 0.01**

- Dex 0.25 mg

- Dex 0.50 mg

## Control (n=14)

**-2**

**-1**

**0**

**1**

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**Delta  AM-PM Cortisol**

**Control (n=14)**

**FM (n=17)**

***p***** = 0.05**

***p***** = 0.009**

- Baseline

- Post

## Autonomic Nervous System

- Number of studies also suggesting altered sympathetic and sympathoadrenal dynamic variability1
- Reduced heart rate variability2
- Altered stimulus-induced blood flow3
- Altered stimulus-induced ANS4

- 1 Petzky & Clauw Curr Rheum Rep 2000; 2:116;  2Martinez-Lavin A&R 1998; 41:1966;
- 3Granges & Littlejohn J Rheumtol 1993;20:344; 4Adler et al.  Am J Med 1999;106:534

## Altered Dynamic Function of Stress-Response Systems 

- Hypo- and hyper-responsiveness may cause similar symptoms
- Concept of allostat
- Function may differ under different physical and psychosocial stress
- Concept of allostatic load
- Strong drive to maintain overall hormone levels
- Current therapies influence expression of key components of system
- TCA and SSRI influence expression of MR/GR in CNS
- Exercise modulates “set point” of allostat

## Implications for Drug Therapy

- FMS is a clinically recognizable syndrome
- Does not exclude the likelihood of subsets of patients with different underlying mechanisms
- Clinically important improvements in pain are likely to occur in response to treatments addressing central mechanisms
- Reduced pain is likely to improve HR-QOL
- Non-pain symptoms are also important to HR-QOL, health-care seeking/utilization
- Non-pain symptoms often cluster with central pain and neurobiological mechanisms may be shared
- Clinically significant improvement in non-pain symptoms likely to result in global improvement