Post on 28-Dec-2015
Manfred Harth MD FRCPCProfessor Emeritus U.W.O
Honoraria from :
Solvay
Jansen-Ortho
Pfizer,
Bristol-Myers Squibb
Boehringer Ingelheim
Review board for a Fralex trial
Grant support from Eli Lilly.
IMEs for several legal firms ,insurance
companies,and WSIAT.
Potential Conflicts of Interest
Betty M., a 50 year old woman, has developed
pain in her neck, shoulders, elbows, forearms,
low back, thighs, knees, ankles and feet over the
past year.
She has fatigue, and a non-refreshing sleep.
We therefore immediately suspect that Betty hasWe therefore immediately suspect that Betty has ::
aa) ) Polymyalgia RheumaticaPolymyalgia Rheumatica
b) Rheumatoid Arthritis
c) Fibromyalgia
d) Galloping hypochondriasis
Fibromyalgia (Fibromyalgia Syndrome)
is a condition characterized by chronic
pain, fatigue, and a non-refreshing sleep.
So, she has Fibromyalgia ?
Prove it !
ACR Classification Criteria
At least 3 regions of chronic pain (> 3 months) :
1 above the waist ;
1 below the waist ;
1 on each side of the body ;
1 in the centre of the body.
+ > 11/18 tender points
Betty M has 16 TPs
Betty M has Fibromyalgia
FM occurs in all ethnic groups,
all over the world.
Its prevalence is 2-4%
About 85% of patients are women
The highest prevalence is between
40-60 years of age.
Associated Disorders
Chronic Fatigue Syndrome
Migraine
Irritable bowel syndrome
Irritable bladder
Restless leg syndrome
Anxiety state
Depression
Associated DiseasesAssociated Diseases
Endometriosis
RA
SLE
AIDS
Lyme Disease
Hepatitis C
Where is the Problem ?
Central Nervous Central Nervous System SensitizationSystem Sensitization
Refers to hyperexcitablility of certain Refers to hyperexcitablility of certain spinal cord nerve cellsspinal cord nerve cells
Characterized by Characterized by spontaneous spontaneous activity, enlarged receptive fields and activity, enlarged receptive fields and increased response to sensory inputincreased response to sensory input
Pain related to central sensitization Pain related to central sensitization does not follow the normal pattern of does not follow the normal pattern of “nerve territories” (dermatomal “nerve territories” (dermatomal distribution)distribution)
Sensory Nerve (First Order)
Second Order Nerve
hyperexcitable
Thalamus
Cerebral Cortex
Spinal Cord
Nociceptors
Normal
Sensitized
Central Sensitization Central Sensitization (cont’d)(cont’d)
Is relevant to FM because it is Is relevant to FM because it is often associated with extensive often associated with extensive secondary hyperalgesia and secondary hyperalgesia and allodynia allodynia
Allodynia = pain due to a stimulus that doesn’t normally provoke pain
Several studies (e.g., Staud et al., 2002; 2003) suggest abnormalities in spinal cord processes in FM
Quantitative Sensory Testing uses the nociceptive flexion reflex R-III (NFR)
• Stimulate Sural nerve (pain pathway)
• Measure latency of biceps femoris response
Median NFR:Median NFR:• FMS patients median threshold = FMS patients median threshold =
22.7 mA (range 17.5-31.7)22.7 mA (range 17.5-31.7)• Normal controls median threshold Normal controls median threshold
= 33 mA (range 28.1-41.0)= 33 mA (range 28.1-41.0)• FMS vs NC : p<0.001FMS vs NC : p<0.001
Suggest hyperexcitability of Suggest hyperexcitability of spinal cord pain mechanisms in spinal cord pain mechanisms in FMS (allodynia)FMS (allodynia)
Brain Imaging Brain Imaging Research in FMResearch in FM
Normal Control Fibromyalgia
DB Cook et al J Rheumatol 2004; 31:364-78
fMRI response to painful heat
Normal Control Fibromyalgia
Deficient in FM
Normal controls show activation of rostral anterior cingulate cortex (A), and pulvinar nucleus of thalamus (B) during painful stimulation.
K B Jensen et al Pain 2009;144:95-100;
Adapted from I J Russell et al Arthritis Rheum 1994;37:1593-1601
Nerve growth factor in CSF
Adapted from SL Giovengo et al J Rheumatol 1999;26:1564-9
0
5
10
15
20
25
30
35
40
45
ControlsFMS
24 hour growth hormone (GH) levels
A Leal-Cerro et al J Clin Endocrinol Metab 1999; 84:3378-81
Effects of IL-6 on NE blood levels
FMS
Normal controls
DJ Torpy et al Arthritis Rheum 2000; 43: 872-80
Half the patients with FMS have
phasic alpha sleep (compared to 7% of controls).
All of these have a non-refreshing sleep.*
* S Roizenblatt et al Arthritis and Rheum 2001; 44:222-30
Brain activity and sleep in FMS
Serotonin, Dopamine, GABA, Glutamate etc…
Betty does not want to use medications at this stage.
" What else can I do other than take
drugs ??? "
ENERGY, PAIN RELIEF,WORK CAPACITYENERGY, PAIN RELIEF,WORK CAPACITY
L Brosseau, Wells GA, Tugwell P et al. Physical Thrapy 2008; 88: 857-71
Brosseau L et al. Ottawa Panel evidence-based clinical Brosseau L et al. Ottawa Panel evidence-based clinical practice guidelines for strengthening exercises in the practice guidelines for strengthening exercises in the management Phys Ther. 2008 Jul;88(7):873-86management Phys Ther. 2008 Jul;88(7):873-86
Pain, Disability, DepressionPain, Disability, Depression
Exercise
• Includes aerobic exercise, flexibility and strength training
• No consensus about what type,duration or intensity are best
Cognitive behavioural therapy ( CBT )Kati Thieme,Dennis Turk,Herta Flor
Arthritis Care Res 2007;57:830-6
3 FM groups (40-43)
CBT, OBT, Attention placebo (AP)
CBT:focus on patient thinking, problem solving, relaxation.
Operant-behavioural therapy : focus on pain behaviour rather than on thought.
15 weekly sessions of 2 hrs each
p<0.001
p<0.005
% ge with clinically significant
reduction or increase in pain
at 12 months
% ge with clinically significant
reduction or increase in physical impairment at 12 months
Betty improves somewhat, but stillcomplains of pain and fatigue.
She is ready now to accept the use of medications
"What choices have I got ? "
μ opioid receptoragonist Has GABAergic,serotonergic andnoradrenergic effects
Tramadol
Acts on opioid receptors in brain
Inhibits serotonin and norepinephrine reuptake,therefore interferes with pain transmission in spinal cord
Available in Canada as Tramadol slow release, or with acetaminophen (Tramacet)
Tramadol and Acetaminophen
Effect on pain
0
10
20
30
40
50
60
70
80
BaselineAt 90 days
T+A Placebo
Pain
score
in mm p < 0.001<
RM Bennett et al Am J Med 2003;114:537-45
AMITRIPTYLINE CYCLOBENZAPRINEAMITRIPTYLINE CYCLOBENZAPRINE
& FRIENDS& FRIENDS
PlaceboPlacebo
CyclCycl
AmiAmi
S Carette et al Arthritis Rheum 1994; 37:32-40S Carette et al Arthritis Rheum 1994; 37:32-40
Cyclobenzaprine
Amitriptyline
Placebo
Gabapentin and Pregabalin
BLOCK
Blockage of α2δ subunit in Ca channel. Reduced release of glutamate,serotonin,noradrenalin,dopamine, substance P.
Pregabalin 13 weeks
PAIN
PJ Mease et al J Rheumatol 2008; 35:502-14
Patient global impression of change-PGIC
Dropouts 33-41%
Pregabalin: Adverse EffectsPregabalin: Adverse Effects
DizzinessDizziness
SomnolenceSomnolence
HeadachesHeadaches
Weight gainWeight gain
EdemaEdema
FIQ improved in 1 trialFIQ improved in 1 trial
Duloxetine over 6 monthsDuloxetine over 6 months
Improvement in painImprovement in pain
Duloxetine -Patient Global ImprovementDuloxetine -Patient Global Improvement
I J Russell et al Pain 2008;136:432-44I J Russell et al Pain 2008;136:432-44
50-55% of patients dropped out 50-55% of patients dropped out over 6 monthsover 6 months
Adverse effects : nausea,dry Adverse effects : nausea,dry mouth, constipation,insomniamouth, constipation,insomnia
Other treatmentsOther treatments
•Electroacupuncture
•Gabapentin
•Pramipexole
•Nabilone
•Milnacipran ( not available in Canada)
•Raloxifen
•Sodium oxybate
•Fluoxetine (large doses)
No evidence for efficacyNo evidence for efficacy
NSAIDs
Narcotics
All antidepressants not mentioned above
Tender point injections
Drugs
Aerobic
exercise
CBT
Education
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