Moving Towards a Mechanistic Characterization of Chronic Pain Dan Clauw M.D.

1. Moving Towards a Mechanistic Characterization of Chronic PainDan Clauw M.D.

2. Laboratory and radiographic/-oscopic evaluation Abnormality identified Cause for pain found (?) Typical Diagnostic Paradigm of Chronic Pain Patient Pain

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. 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?

7. 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 Stimulus

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. 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 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 % of Population 16 14 12 10 8 6 4 2 0 Tenderness

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. Brain and Spinal Influences on Pain Processing Volume Volume • Descending analgesic pathways • Norepinephrine – serotonin (5HT1a,b) • Opioids • GABA • Cannabanoids • Adenosine • Substance P • Glutamate and EAA • Serotonin (5HT2a, 3a) • Neurotensin • Nerve growth factor • CCK +

16. 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 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.

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. Chronic Pain Disorders High State of Pain Amplification High Psychological Distress ENVIRONMENTAL CONTRIBUTION Mood Tissue Injury Impaired Pain Regulatory Systems Pro-inflammatory State Stress Response Anxiety Blood Pressure Somatization Depression Serotonin transporter Na+, K+-ATPase Cannabinoid receptors Dopamine receptors GAD65 NET CACNA1A IKK COMT Serotonin receptor Opioid receptors Adrenergic receptors MAO NMDA GR DREAM POMC BDNF NGF Prodynorphin Interleukins CREB1 Xp11.23 12q11.2 9q34.3 11q23 5q31-q32 6q24-q25 1p13.1 22q11.21 5q31-32 Diatchenko et al, Pain, 2006

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 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

24. 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? Treatment of Idiopathic/Central Pain Syndromes

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