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  • 1. Moving Towards a Mechanistic Characterization of Chronic Pain Dan Clauw M.D.
  • 2. Typical Diagnostic Paradigm of Chronic Pain Patient Pain Cause for pain found (?) Abnormality identified Laboratory and radiographic/-oscopic evaluation
  • 3. How is Chronic Pain Typically Managed? Acute Pain Model
    • Look for “cause” of pain
      • X-ray, MRI, or – oscopy
    • Treat with medications
      • Acetaminophen (Tylenol)
      • Nonsteroidal drugs (Nuprin, Alleve, Celebrex, etc.)
      • Narcotics
    • If this doesn’t work, we have a tendency to:
      • blame (drug-seeking, somatizer, high health care utilizer, difficult patient, psychiatric)
      • ignore
      • refer
    • Inject it, or cut it out and fix/replace it
  • 4. Why Are So Many Patients Left With Chronic Pain?
    • Current paradigms are based on the antiquated notion that chronic pain is a symptom , and merely represents acute pain that has lasted too long
    • Recent research has indicated that chronic pain is a disease
    • Most chronic pain that is “left over” after our current treatments, is not due to damage or inflammation of peripheral tissues, but instead due to:
      • A disturbance in the way the nervous system is processing pain signals
      • How the individual behaviorally/cognitively responds to the pain
  • 5. Current Taxonomy for Chronic Pain Syndromes
    • By “disease”
      • Autoimmune disorders
      • Cancer pain
      • Overuse or “wear-and-tear”
        • Osteoarthritis
        • Low back pain
      • Miscellaneous endocrine or neurological disorders
    • By location
      • “Idiopathic” disorders
  • 6. What’s Causing Chronic Pain?
    • Idiopathic Pain Syndromes
    • e.g. fibromyalgia, headaches, irritable bowel
    • 15 – 20% of population have sx. severe enough to seek medical attention
    • frequently co-exist with inflammatory and mechanical disorders
    • Mechanical or
    • “ Wear-and-tear”
    • Disorders
    • e.g. osteoarthritis
    • prevalence very age-dependant
    • Autoimmune and
    • Inflammatory
    • Disorders
    • e.g. rheumatoid arthritis, lupus
    • 2 – 3 % of population
  • 7. Fallacies about Chronic Pain
    • Most chronic pain is due to
    • damage or inflammation
    • of peripheral structures
    Stimulus Spinal cord from Robert Bennett, MD A-delta – 1 st sharp C fiber – 2 nd burning, throbbing Willis 1985
  • 8. Pain in SLE (Lupus)
    • 20 – 25% of patients with SLE and other autoimmune disorders have co-morbid fibromyalgia (Clauw 1995)
    • Frequently there is discordance between patient ratings of disease activity and physician’s ratings (Neville 2000)
    • Little or no correlation between objective measures of disease activity (e.g. SLEDAI) or damage (SLICC/ACR) and pain/function; presence of co-morbid FM is best predictor of pain, function (Gladman 1997)
  • 9. Pain in Osteoarthritis
    • 10% of individuals with knee pain have normal radiographs (Baltimore Longitudinal Study of Aging - Lethridge-Cejku 1995)
    • 30 – 60% of patients with severe osteoarthritis (K-L stages III, IV) have no pain (BLAS - Hochberg 1989; Tecumseh - Carman 1989; Framingham - Felson 1987)
    • More sophisticated imaging studies are more expensive but not more predictive of pain
    • Psychiatric factors (anxiety, depression) can only explain a small percentage of the variance in pain ( Creamer 1999 )
  • 10. Chronic Low Back Pain
    • Generally acknowledged to be the most common and expensive musculoskeletal problem in developed countries
    • Abnormal MRI are common in asymptomatic individuals (52% at least one bulging disc, 27% with disc protrusion, 38% > one level abnl.) (Jensen 1994)
    • 50 – 80% of CLBP judged to be “idiopathic” (Deyo 2001)
    • Psychological factors can only explain a small percentage of the variance in pain and function seen in CLBP
  • 11. Idiopathic disorders Defined largely by location
    • Tension/migraine headache
    • Temporomandibular joint syndrome
    • Regional musculoskeletal pain (e.g., chronic cervical or lumbar pain, whiplash, tendinitis/ “tendinosis”, myofascial pain syndrome)
    • “ Chronic “sinusitis”
    • “ Burning mouth” syndrome
    • Esophageal dysmotility, non-cardiac chest pain, “Syndrome X”, costochondritis
    • Biliary dyskinesia, post-cholecystectomy syndrome
    • Interstitial cystitis, female urethral syndrome, vulvar vestibulitis, vulvodynia
    Irritable bowel syndrome
  • 12. What Causes Idiopathic Pain Syndromes? Fibromyalgia as a Model
    • Genes
    • “ Stress”
    • Cognitive and behavioral adaptation
    • to acute symptoms
  • 13. Pain Sensitivity in the General Population
    • We all have a “volume control” setting for how our brain and spinal cord processes pain
    • This is likely set by the genes that we are born with, and modified by the environment that we grow up in and live in
    • The higher the volume control setting, the more pain we will experience
    • The most commonly used drugs to treat pain do little to change this “volume” setting
    0 2 4 6 8 10 12 14 16 Tenderness % of Population
  • 14. Using Experimental Pain Testing to Examine Pain Processing
    • Hyperalgesia / allodynia distant from site of pain
      • FM (Petzke/Clauw/Gracely; Geisser/Casey/Crofford)
      • IBS (Mayer, Naliboff, Chung; Whitehead)
      • TMD (Maixner; Kashima)
      • Tension HA (Langemark)
      • Low back pain (Giesecke)
      • Vulvodynia/vulvar vestibulitis (Giesecke/Reed)
    • Potential Mechanisms in FM
      • Wind-up in FM (Price, Staud)
      • Absence of DNIC (Kosek; Marchand)
  • 15.
    • Volume
    + Volume Brain and Spinal Influences on Pain Processing
    • Substance P
    • Glutamate and EAA
    • Serotonin (5HT 2a, 3a )
    • Neurotensin
    • Nerve growth factor
    • CCK
    • Descending analgesic pathways
      • Norepinephrine – serotonin (5HT 1a,b )
      • Opioids
    • GABA
    • Cannabanoids
    • Adenosine
  • 16. Which Endogenous Analgesic System(s) are Attenuated in Fibromyalgia?
    • Opioids
    • Normal or high levels of CSF enkephalins 1
    • Never been administered in RCT but most feel that opioids are ineffective or marginally effective
    • Noradrenergic/Serotinergic
    • Low levels of biogenic monoamines in CSF in FM 2
    • Nearly any class of drug that raises both serotonin and norepinephrine has demonstrated efficacy in FM
    • Baraniuk et al. BMC Musculoskelet Disord . 2004;5:48.
    • Russell et al. Arthritis Rheum . 1992;35:550-556.
  • 17. The Genomics of Pain
    • Different strains of animals have different pain sensitivity, and pain sensitivity can be modified in “knock-out” mice (Mogill)
    • In 2002, the first demonstration that a genetic polymorphism in the COMT gene caused differences in pain sensitivity in humans (Zubieta)
    • In 2005, the first study demonstrated that pain-free individuals with this gene who were followed for two years, were at higher risk of developing pain (Diatchenko)
    • In the next 3 – 5 years, we will likely identify 20 – 30 genes that control both stress responsivity and pain sensitivity of an individual, and be able to place this on a “chip” that can be used to determine this profile in an individual
    • This will likely cost approximately as much as a single MRI scan
  • 18. Diatchenko et al, Pain, 2006 ENVIRONMENTAL CONTRIBUTION High Psychological Distress High State of Pain Amplification Anxiety Depression Stress Response Impaired Pain Regulatory Systems Pro-inflammatory State Blood Pressure Na+, K+-ATPase Serotonin transporter BDNF 12q11.2 Cannabinoid receptors MAO 11q23 Adrenergic receptors NMDA POMC COMT Interleukins 5q31-32 22q11.21 Opioid receptors Prodynorphin DREAM NGF IKK NET Somatization Tissue Injury CREB1 Serotonin receptor GR Dopamine receptors Mood GAD65 CACNA1A Chronic Pain Disorders 6q24-q25 1p13.1 5q31-q32 9q34.3 Xp11.23
  • 19. What Causes Idiopathic Pain Syndromes? Fibromyalgia as a Model
    • Genes
    • “ Stress”
    • Cognitive and behavioral adaptation
    • to acute symptoms
  • 20. “ Stressors” Capable of Triggering These Illnesses (Supported by Case-Control Studies)
    • Peripheral pain syndromes
    • Infections (eg, parvovirus, EBV, Lyme disease, Q fever; not common URI)
    • Physical trauma (automobile accidents)
    • ? Psychological stress/distress
    • Hormonal alterations (eg, hypothyroidism)
    • Vaccines
    • Certain catastrophic events (some wars, but not natural disasters)
    Clauw et al. Neuroimmunomodulation . 1997;4:134-153; McLean et al. Med Hypotheses. 2004;63:653-658.
  • 21. “ Stress” Related Syndromes Susceptible Individuals Exposure to “Stressors” Mood Disorder PTSD Idiopathic or central pain/fatigue syndrome
  • 22. What Causes Idiopathic Pain Syndromes? Fibromyalgia as a Model
    • Genes
    • “ Stress”
    • Cognitive and behavioral adaptation
    • to acute symptoms
  • 23. Drugs or surgery can address Non-drug therapies needed to address
    • Functional Consequences of Symptoms
    • Distress
    • Decreased activity
    • Isolation
    • Poor sleep
    • Maladaptive illness behaviors
    • Initial Symptoms of Pain
      • Damage or inflammation of tissues
      • Disordered sensory processing
  • 24. Treatment of Idiopathic/Central Pain Syndromes
    • Education
    • Pharmacological therapy
    • Aerobic exercise
    • Cognitive behavioral therapy (CBT)
    • ? Alternative therapies
    • Not reimbursed
    • Use wrong drugs e.g. NSAIDs / opioids
    • Not reimbursed
    • Not reimbursed
    • May be working primarily via placebo effect, but is that so bad?
  • 25. Change in Pain Over Time in Drug Trial Improvement due to “placebo” Improvement due to drug
  • 26. How Can We Use This Information To Take Better Care of Chronic Pain Patients Now ?
    • Identify patients with “central pain” early and manage them differently
    • Pain not well localized and/or multifocal
    • “ Peripheral” factors inadequate to account for pain
    • Diffuse tenderness
    • Accompanying somatic symptoms or syndromes
    • Refractory to standard therapies
  • 27. Tools for Future “Personalized Medicine” in Chronic Pain
    • Diagnosis
    • Genomics
    • Clinical sensory testing
    • Functional imaging
    • Treatment
    • Better drugs
    • Genomics
    • Web-enabled self-management and feedback programs