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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