Moving Towards a Mechanistic Characterization of Chronic Pain
Dan Clauw M.D.
Typical Diagnostic Paradigm of Chronic Pain Patient
Pain
Laboratory and radiographic/-oscopic evaluation
Abnormality identified
Cause for pain found (?)
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?
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 agedependant
Fallacies about Chronic Pain
• Most chronic pain is due to damage or inflammation of peripheral structures
A-delta – 1st sharp C fiber – 2nd burning, throbbing Willis 1985
Stimulus
Spinal cord
from Robert Bennett, MD
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) Irritable bowel syndrome
“Chronic “sinusitis”
“Burning mouth” syndrome Esophageal dysmotility, noncardiac chest pain, “Syndrome X”, costochondritis Biliary dyskinesia, postcholecystectomy syndrome Interstitial cystitis, female urethral syndrome, vulvar vestibulitis, vulvodynia
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
% of Population 16 14
12
10 8 6 4
2
0 Tenderness
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
Volume
• • • • • • Substance P Glutamate and EAA Serotonin (5HT2a, 3a) Neurotensin Nerve growth factor CCK
Volume
• Descending analgesic pathways – Norepinephrine – serotonin (5HT1a,b) – Opioids • GABA • Cannabanoids • Adenosine
+
Which Endogenous Analgesic System(s) are Attenuated in Fibromyalgia?
Opioids
Noradrenergic/Serotinergic
• Normal or high • Low levels of biogenic levels of CSF monoamines in CSF in FM2 enkephalins1 • Nearly any class of drug that • Never been raises both serotonin and administered in RCT norepinephrine has but most feel that demonstrated efficacy in FM opioids are ineffective or 1. Baraniuk et al. BMC Musculoskelet Disord. 2004;5:48. marginally effective
2. Russell 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
Chronic Pain Disorders
ENVIRONMENTAL CONTRIBUTION
High Psychological Distress
High State of Pain Amplification
Mood Anxiety Depression
GAD65 Serotonin MAO receptor
Stress Response
Tissue Injury Somatization Blood Pressure
Impaired ProPain inflammatory Regulatory State Systems
Serotonin Na+, K+Cannabinoid Dopamine transporte CACNA1A NET IKK COMT ATPase receptors receptors Opioid Adrenergic r NMDA GR receptors DREAM POMC CREB1 receptors BDNF NGF Prodynorphi Interleukins n
Xp11.23
12q11.2 9q34.3
11q23
5q31-q32
5q31-32
6q24-q25
1p13.1
22q11.21
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. Neuroimmunomodulation. 1997;4:134-153; McLean et al. Med Hypotheses. 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
Initial Symptoms of Pain
Damage or inflammation of tissues Disordered sensory processing
Drugs or surgery can address
Functional Consequences of Symptoms
Distress Decreased activity Isolation Poor sleep Maladaptive illness behaviors
Non-drug therapies needed to address
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
0 -2 -4 -6 -8 -10 -12 -14 -16 -18 -20 0 5 10 15 20 25 30
Improvement due to “placebo”
Placebo 100 mg 200 mg
Improvement due to drug
Week
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 Treatment
• Better drugs
• Genomics
• Clinical sensory testing • Functional imaging
• Genomics
• Web-enabled selfmanagement and feedback programs