Moving Towards a Mechanistic

Characterization of Chronic Pain

Dan Clauw M.D.

Typical Diagnostic Paradigm of Chronic Pain Patient

Pain

Cause for pain found (?)

Abnormality identified

Laboratory and radiographic/-oscopic evaluation

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?

• 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

• By “disease”– Autoimmune disorders– Cancer pain– Overuse or “wear-and-tear”

• Osteoarthritis• Low back pain

– Miscellaneous endocrine or neurological disorders

• By location– “Idiopathic” disorders

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

Fallacies about Chronic Pain

• Most chronic pain is due to

damage or inflammation

of peripheral structures

StimulusSpinal cord

from Robert Bennett, MD

A-delta – 1st sharp

C fiber – 2nd burning, throbbing

Willis 1985

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• 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

• 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

Irritable bowel syndrome

What Causes Idiopathic Pain Syndromes?

Fibromyalgia as a Model

• Genes

• “Stress”

• Cognitive and behavioral adaptation

to acute symptoms

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

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10

12

14

16

Tenderness

% of Population

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)

Volume

+

Volume

Brain and Spinal Influences on Pain Processing

• Substance P• Glutamate and EAA

• Serotonin (5HT2a, 3a)

• Neurotensin• Nerve growth factor • CCK

• Descending analgesic pathways – Norepinephrine –

serotonin (5HT1a,b)

– Opioids• GABA• Cannabanoids• Adenosine

Which Endogenous Analgesic System(s) are Attenuated in

Fibromyalgia?Opioids• Normal or high levels

of CSF enkephalins1

• 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 FM2

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

1.1. Baraniuk et al. Baraniuk et al. BMC Musculoskelet DisordBMC Musculoskelet Disord. 2004;5:48.. 2004;5:48.2.2. RussellRussell et al. Arthritis Rheum. 1992;35:550-556.

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

EN

VIR

ON

ME

NT

AL

CO

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RIB

UT

ION

High Psychological

Distress

High State of Pain

Amplification

Anxiety

Depression

Stress Response

Impaired Pain

Regulatory Systems

Pro-inflammatory

StateBlood Pressure

Na+, K+-ATPase

Serotonin transporter

BDNF

12q11.2

Cannabinoid receptors

MAO

11q23

Adrenergic receptorsNMDA POMC

COMT

Interleukins

5q31-32 22q11.21

Opioid receptors Prodynorphi

nDREAM NGF

IKKNET

Somatization

Tissue Injury

CREB1

Serotoninreceptor GR

Dopamine receptors

Mood

GAD65 CACNA1A

Chronic Pain Disorders

6q24-q25 1p13.1 5q31-q32 9q34.3 Xp11.23

Diatchenko et al, Pain, 2006

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)• 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. Clauw et al. NeuroimmunomodulationNeuroimmunomodulation. 1997;4:134-153; McLean et al.. 1997;4:134-153; McLean et al. Med Hypotheses. Med Hypotheses. 2004;63:653-658.2004;63:653-658.

“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 Model

• Genes

• “Stress”

• Cognitive and behavioral adaptation

to acute symptoms

Drugs or surgery can

address

Non-drug therapies needed to address

Functional Consequences Functional Consequences

of Symptomsof Symptoms DistressDistress Decreased activityDecreased activity IsolationIsolation Poor sleepPoor sleep Maladaptive illnessMaladaptive illness

behaviorsbehaviors

Initial Symptoms of PainInitial Symptoms of Pain

Damage or inflammation of tissuesDamage or inflammation of tissues Disordered sensory processingDisordered sensory processing

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?

Change in Pain Over Time in Drug Trial

Daily Morning Report Scores- Change from Baseline

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-18

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-2

0

0 5 10 15 20 25 30

Week

Placebo

100 mg

200 mgImprovement Improvement

due to due to “placebo”“placebo”

Improvement due to drugImprovement due to drug

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

Diagnosis• Genomics• Clinical sensory testing• Functional imaging

Treatment• Better drugs • Genomics• Web-enabled self-management and feedback programs