moving towards a mechanistic characterization of chronic pain dan clauw m d n.
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Moving Towards a Mechanistic Characterization of Chronic Pain Dan Clauw M.D. Laboratory and radiographic/-oscopic evaluation. Abnormality identified. Cause for pain found (?). Typical Diagnostic Paradigm of Chronic Pain Patient. Pain.

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how is chronic pain typically managed acute pain model
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
why are so many patients left with chronic pain
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
current taxonomy for chronic pain syndromes
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

Autoimmune and

  • Inflammatory
  • Disorders
  • e.g. rheumatoid arthritis, lupus
  • 2 – 3 % of population
  • 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

What’s Causing Chronic Pain?

fallacies about chronic pain

A-delta – 1st sharp

C fiber – 2nd burning, throbbing

Willis 1985

Spinal cord

from Robert Bennett, MD

Fallacies about Chronic Pain
  • Most chronic pain is due to

damage or inflammation

of peripheral structures


pain in sle lupus
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)
pain in osteoarthritis
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)
chronic low back pain
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
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

Idiopathic disorders Defined largely by location

Irritable bowel


what causes idiopathic pain syndromes fibromyalgia as a model
What Causes Idiopathic Pain Syndromes?Fibromyalgia as a Model
  • Genes
  • “Stress”
  • Cognitive and behavioral adaptation

to acute symptoms

pain sensitivity in the general population
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

% of Population











using experimental pain testing to examine pain processing
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)

Brain and Spinal Influences

on Pain Processing



  • Descending analgesic pathways
    • Norepinephrine – serotonin (5HT1a,b)
    • Opioids
  • GABA
  • Cannabanoids
  • Adenosine
  • Substance P
  • Glutamate and EAA
  • Serotonin (5HT2a, 3a)
  • Neurotensin
  • Nerve growth factor
  • CCK


which endogenous analgesic system s are attenuated in fibromyalgia

Normal or high levels of CSF enkephalins1

Never been administered in RCT but most feel that opioids are ineffective or marginally effective


Low levels of biogenic monoamines in CSF in FM2

Nearly any class of drug that raises both serotonin and norepinephrine has demonstrated efficacy in FM

Which Endogenous Analgesic System(s) are Attenuated in Fibromyalgia?
  • Baraniuk et al. BMC Musculoskelet Disord. 2004;5:48.
  • Russell et al. Arthritis Rheum. 1992;35:550-556.
the genomics of pain
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

Chronic Pain Disorders

High State of Pain Amplification

High Psychological Distress



Tissue Injury

Impaired Pain Regulatory Systems

Pro-inflammatory State

Stress Response


Blood Pressure



Serotonin transporter

Na+, K+-ATPase

Cannabinoid receptors

Dopamine receptors








Opioid receptors

Adrenergic receptors




















Diatchenko et al, Pain, 2006

what causes idiopathic pain syndromes fibromyalgia as a model1
What Causes Idiopathic Pain Syndromes?Fibromyalgia as a Model
  • Genes
  • “Stress”
  • Cognitive and behavioral adaptation

to acute symptoms

stressors capable of triggering these illnesses supported by case control studies
“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.

stress related syndromes
“Stress” Related Syndromes

Susceptible Individuals

Exposure to “Stressors”

Mood Disorder PTSD Idiopathic or central pain/fatigue syndrome

what causes idiopathic pain syndromes fibromyalgia as a model2
What Causes Idiopathic Pain Syndromes?Fibromyalgia as a Model
  • Genes
  • “Stress”
  • Cognitive and behavioral adaptation

to acute symptoms

drugs or surgery can address non drug therapies needed to address
Drugs or surgery can addressNon-drug therapies needed to address

Initial Symptoms of Pain

  • Damage or inflammation of tissues
  • Disordered sensory processing

Functional Consequences of Symptoms

  • Distress
  • Decreased activity
  • Isolation
  • Poor sleep
  • Maladaptive illness behaviors
treatment of idiopathic central pain syndromes

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?

Treatment of Idiopathic/Central Pain Syndromes
change in pain over time in drug trial
Change in Pain Over Time in Drug Trial

Improvement due to “placebo”

Improvement due to drug

how can we use this information to take better care of chronic pain patients now
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
tools for future personalized medicine in chronic pain
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