E N D
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