Co-Management of Juvenile Fibromyalgia and Chronic Fatigue Syndrome

1. Co-Management of Juvenile Fibromyalgia and Chronic Fatigue Syndrome Lawrence Zemel, MD Chief, Division of Rheumatology CCMC

3. Musculoskeletal Pain (MSP) 6% of visits to a pediatric primary clinic of children>3 y/o was for MSP De Inocencio Pediatrics 1998 Low back pain 1 month prevalence in UK among 1496 students 11-14 years old was 24% (pain for >1 day), 94 % reported disability via a disability questionnaire Watson Arch Dis Child 2003

4. Pain/ Discomfort in Adolescent Girls in the US School based cross sectional survey of 6th –10th grade girls in US 29.1% headache 20.7% stomachache 23.6% back pain 30.6% more fatigue >once /week 53% of the>1/wk headache sufferers also reported stomachache>1/wk; 74.3% morning fatigue >1/wk Ghandour Arch Pediatr Adolesc Med 2004

5. Childhood Pain Syndromes 25% of all new patients seen by pediatric rheumatologists 75% female Average age of onset 12 years

6. Pro-Nociceptive Influences(Hyperalgesia or Allodynia)

7. Antinociceptive Influences

8. Chronic MSP/Central Pain Processing and Related Disorders Fibromyalgia Chronic Fatigue Migraine Irritable Bowel Syndrome TMJ disorders Mood Disorders Complex Regional Pain Syndrome (RSD) Chronic Pelvic Pain Premenstrual Syndrome Myofascial Pain syndromes Multiple Chemical Sensitivities Chronic cystitis Dysautonomia/ POTS

9. Chronic Fatigue Syndrome Clinically evaluated, unexplained, persistent or relapsing fatigue for >3 months that is of new or definite onset and that: is not the result of exertion, not alleviated by rest, and results in disability Exclude other causes of fatigue, inclu- ding major psychiatric disease

11. Symptom Criteria for CFS sore throat tender nodes myalgia arthralgia headache non-restorative sleep post exertional malaise impaired cognition

13. Treatment of CFS Lifestyle changes Cognitive-behavioral therapy Graded exercise program SNRI’s Stimulants No evidence for: IVIg, prednisone, anti-viral therapy

15. Symptoms of Postural Orthostatic Tachycardia Syndrome mental clouding (“brain fog”), blurred or tunneled vision, shortness of breath, palpitation, tremulousness, chest discomfort, headache, lightheadedness and nausea syncope (30%) or pre-syncope

20. Juvenile Fibromyalgia (JFS) Widespread MSP for at least 3 months > 5 well-defined tender points 3 of 10 minor criteria < age 16 at onset

22. Juvenile Fibromyalgia: Minor Criteria Fatigue Sleep problems Anxiety/ tension Subjective swelling Numbness/tingling Lightheadedness/ dizziness Chronic headache Irritable Bowel syndrome Pain modulated by stress Pain modulated by weather Pain modulated by physical activity

23. Juvenile Fibromyalgia 1756 school-aged (pre-adolescent) Finnish children prospectively studied by questionnaire then PE; 1.3% prevalence 338 healthy Israeli 9-15 y/o students studied; 6.2% prevalence 1.3% healthy Mexican 9-15 y/o students

24. Fibromyalgia CSF Substance P

25. Central Pain Processing Disorders & Catastrophizing Responses that characterize pain as being “awful” “horrible”, “unbearable” Found to be independent of Depression May influence intentional focus on painful or potentially painful events Increases pain-related fear leading to increased attention to stimuli and amplifying perception of pain rCBF similar to that found in Fibromyalgia

26. Functional MRI in Chronic Pain States fMRI takes advantage of magnetic moment of deoxygenated blood, and thus can detect neuronal activations associated with stimuli Most imaging sequences take advantage of “on-off” paradigms, where the difference between the blood flow in a “neutral” condition (e.g. touch) and pain is imaged PET and fMRI have identified a number of brain regions involved in pain processing

27. Fibromyalgia & Regional Cerebral Brain Flow Fibromyalgia patients and controls detect sensory stimuli at the same levels (electric, thermal, mechanical) Level at which stimuli become noxious is ~twice as high for controls Similar stimuli produce significant differences in regional Cerebral Brain Flow; >2x’s in pts vs controls, particularly in the Anterior Cingulate Cortex

28. FMS : rCBF

29. Fibromyalgia & Sleep Disturbance Moldofsky noted absence of Stage 4 sleep in FMS pts (intrusion of ? rhythm into non-REM sleep) Healthy volunteers then deprived of stage 4 sleep found to have developed MSP and increased tenderness to pressure

30. Fibromyalgia & Sleep Of the many perturbations in neuroendocrine function found in FMS, a decrease in IGF-1 has been noted IGF-1 is a product of the liver and is provoked by GH, and is decreased by somatostatin, and pro-inflammatory cytokines. IGF-1 and GH are both factors in repair of muscle microtrauma

31. Fibromyalgia & Sleep GH is secreted during deep sleep and following vigorous exercise Somatostatin inhibits IGF-1 and itself is increased by Corticotropin-releasing hormone (?in response to stress in FMS) Catecholamines promote Th1 lymphocyte response that favor production of INF-? and IL-6 (autonomic dysfunction common to FMS)

32. Fibromyalgia & Sleep Disturbance: causes Idiopathic Chronic Inflammatory pain: JRA, SLE etc Obstructive Sleep Apnea Sub-optimal control of asthma, CHF, chronic sinusitis or other cardiorespiratory problems Chronic/ recurrent mechanical pain: hypermobility syndrome, neuromuscular dysfunction (spasticity) Depression Environmental

33. Fatigue & Malaise: Deconditioning Appropriate yet unrealistic expectations Intuitive response Muscle atrophy Loss of aerobic fitness Alteration in normal biorhythm/sleep pattern Encourages a cycle of more rest, inactivity and further deconditioning

34. Fibromyalgia & Hypermobility Association with Juvenile Episodic Arthralgia (40%? in recurrent arthralgia) Prevalence of Hypermobility in school age population (6-12%) Prevalence of hypermobility in an adult FMS population 22.6% Dysautonomia common; POTS found in 78% of hypermobile pts 10% controls ? ?- and ?-adrenergic responsiveness

35. SNP’s and Central Pain Processsing Disorders 3 genes containing SNP’s differentiated CFS vs Control subjects: Neuronal Tryptophan Hydroxylase, Catechol-O-methyltransferase (COMT), and nuclear receptor subfamily 3,group C,member 1 glucocorticoid receptor (NR3C1)…predicted CFS with 76.3% accuracy Pharmacogenetics 7(3):475-83,2006 Apr

36. SNP’s and Central Pain Processing Disorders ? adrenergic receptor polymorphisms found in Spanish and Mexican FMS pts However, a comprehensive review published in 2008 (Rheumatology 47:572) could not conclude that there were definitive susceptibility genes identified due to inadequate sample size

37. Anxiety, Mood and Behavioral Disorders Among Pediatric Patients with JFMS 76 subjects with primary FMS in multicenter study 67.1% at least 1 current DSM IV psychiatric diagnosis 57.5% Anxiety Disorder Major Depression infrequent Kashikar-Zuck et al Clinical Journal of Pain 24:620 September 2008

40. Symptoms and Syndromes Related to Fibromyalgia

41. Treatment of Fibromyalgia and Other Central Pain Syndromes Education Pharmacologic Aerobic Exercise Alternative Therapies Cognitive Behavior Therapy

44. Pharmacologic Therapy Supported by RCT Low doses of tricyclic drugs (e.g. amitriptyline, cyclobenzaprine) best studied SSRIs, NSAIDs ineffective or less effective Mixed noradrenergic/serotinergic agents Atkinson et. Al. Pain 1999: Maprotiline > Paroxetine > Placebo for non-depressed LBP Symptom based therapy Tramadol Gabapentin Pregabalin NSAIDs = nonsteroidal anti-inflammatory drugs; RCT = randomized controlled trials; SSRI = selective serotonin reuptake inhibitors

46. Pharmacologic Treatment of Central Pain Antidepressants Mixed norepinephrine/serotonin reuptake inhibitors (SNRI’s) Anticonvulsants Alpha-2-delta (a2d) ligands Opioid receptor antagonists Future Central alpha-2-adrenergic agonist Dopamine receptor agonists NMDA receptor antagonists NK-1 receptor antagonist GABA receptor agonists

47. Relative Serotonin and Norepinephrine Re-Uptake Amongst Antidepressants

48. Balanced Reuptake Inhibitors Venlafaxine – Considerable off-label use for pain but very few RCT Conflicting results from two trials in FM Milnacipran – Approved as antidepressant and FMS by FDA Duloxetine – Showing activity as antidepressant with focus on treating the pain and somatic symptoms associated with depression

49. Anticonvulsants Diverse class of drugs with actions including Blockade of voltage-gated sodium channels Direct or indirect enhancement of GABA Inhibition of glutamatergic transmission All of these mechanisms have the net effect of reducing hyperexcitable neurons (e.g. in a seizure focus, or a damaged nerve) The first generation of these compounds was primarily useful in neuropathic pain or as mood stabilizer

51. Sleep Hygiene Bed is for sleep only No naps Regular bedtime No vigorous exercise within 2 hrs of bedtime No more than 30 minutes of sleeplessness in bed Relaxation, self-guided imagery techniques

52. Exercise Aerobic nearly universally beneficial; tolerance, compliance, adherence are biggest issues To maximize benefits: Begin several months after pharmacologic therapy Begin with low impact exercises; avoid strength training until late Both physician and patient should consider this as a “drug” Less evidence supporting strengthening, stretching