Manfred Harth MD FRCPC Professor Emeritus U W

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Manfred Harth MD FRCPC Professor Emeritus U. W. O

Manfred Harth MD FRCPC Professor Emeritus U. W. O

Potential Conflicts of Interest Honoraria from : Solvay Jansen-Ortho Pfizer, Bristol-Myers Squibb Boehringer Ingelheim

Potential Conflicts of Interest 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.

Betty M. , a 50 year old woman, has developed pain in her neck,

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 has : a) Polymyalgia Rheumatica b) Rheumatoid Arthritis

We therefore immediately suspect that Betty has : a) Polymyalgia Rheumatica b) Rheumatoid Arthritis c) Fibromyalgia d) Galloping hypochondriasis

Fibromyalgia (Fibromyalgia Syndrome) is a condition characterized by chronic pain, fatigue, and a non-refreshing

Fibromyalgia (Fibromyalgia Syndrome) is a condition characterized by chronic pain, fatigue, and a non-refreshing sleep.

So, she has Fibromyalgia ? Prove it !

So, she has Fibromyalgia ? Prove it !

ACR Classification Criteria At least 3 regions of chronic pain (> 3 months) :

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

+ > 11/18 tender points

Betty M has 16 TPs Betty M has Fibromyalgia

Betty M has 16 TPs Betty M has Fibromyalgia

FM occurs in all ethnic groups, all over the world. Its prevalence is 2

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

Associated Disorders Chronic Fatigue Syndrome Migraine Irritable bowel syndrome Irritable bladder Restless leg syndrome Anxiety state Depression

Associated Diseases Endometriosis RA SLE AIDS Lyme Disease Hepatitis C

Associated Diseases Endometriosis RA SLE AIDS Lyme Disease Hepatitis C

Where is the Problem ?

Where is the Problem ?

Central Nervous System Sensitization n Refers to hyperexcitablility of certain spinal cord nerve cells

Central Nervous System Sensitization n Refers to hyperexcitablility of certain spinal cord nerve cells Characterized by spontaneous activity, enlarged receptive fields and increased response to sensory input Pain related to central sensitization does not follow the normal pattern of “nerve territories” (dermatomal distribution)

Cerebral Cortex Sensory Nerve (First Order) Thalamus Nociceptors hyperexcitab le Second Order Nerve Spinal

Cerebral Cortex Sensory Nerve (First Order) Thalamus Nociceptors hyperexcitab le Second Order Nerve Spinal Cord

Normal Sensitized

Normal Sensitized

Central Sensitization (cont’d) Allodynia = pain due to a n Is relevant to FM

Central Sensitization (cont’d) Allodynia = pain due to a n Is relevant to FM because it is stimulus that doesn’t oftennormally associated with extensive provoke pain secondary hyperalgesia and allodynia Several studies (e. g. , Staud et al. , 2002; 2003) suggest abnormalities in spinal cord processes in FM n

Quantitative Sensory Testing uses the nociceptive flexion reflex R-III (NFR) • Stimulate Sural nerve

Quantitative Sensory Testing uses the nociceptive flexion reflex R-III (NFR) • Stimulate Sural nerve (pain pathway) • Measure latency of biceps femoris response

n Median NFR: • FMS patients median threshold = 22. 7 m. A (range

n Median NFR: • FMS patients median threshold = 22. 7 m. A (range 17. 5 -31. 7) • Normal controls median threshold = 33 m. A (range 28. 1 -41. 0) • FMS vs NC : p<0. 001 n Suggest hyperexcitability of spinal cord pain mechanisms in FMS (allodynia)

Brain Imaging Research in FM

Brain Imaging Research in FM

f. MRI response to painful heat Normal Control Fibromyalgia DB Cook et al J

f. MRI response to painful heat Normal Control Fibromyalgia DB Cook et al J Rheumatol 2004; 31: 364 -78

Normal Control Fibromyalgia

Normal Control Fibromyalgia

Deficient in FM

Deficient in FM

Normal controls show activation of rostral anterior cingulate cortex (A), and pulvinar nucleus of

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

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;

Nerve growth factor in CSF Adapted from SL Giovengo et al J Rheumatol 1999; 26: 1564 -9

24 hour growth hormone (GH) levels A Leal-Cerro et al J Clin Endocrinol Metab

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

Effects of IL-6 on NE blood levels FMS Normal controls DJ Torpy et al Arthritis Rheum 2000; 43: 872 -80

Brain activity and sleep in FMS Half the patients with FMS have phasic alpha

Brain activity and sleep in FMS 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

Serotonin, Dopamine, GABA, Glutamate etc…

Serotonin, Dopamine, GABA, Glutamate etc…

Betty does not want to use medications at this stage. " What else can

Betty does not want to use medications at this stage. " What else can I do other than take drugs ? ? ? "

ENERGY, PAIN RELIEF, WORK CAPACITY L Brosseau, Wells GA, Tugwell P et al. Physical

ENERGY, PAIN RELIEF, WORK CAPACITY L Brosseau, Wells GA, Tugwell P et al. Physical Thrapy 2008; 88: 857 -71

Pain, Disability, Depression Brosseau L et al. Ottawa Panel evidence-based clinical practice guidelines for

Pain, Disability, Depression Brosseau L et al. Ottawa Panel evidence-based clinical practice guidelines for strengthening exercises in the management Phys Ther. 2008 Jul; 88(7): 873 -86

Exercise • Includes aerobic exercise, flexibility and strength training • No consensus about what

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

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 % ge with clinically significant reduction or increase in pain at 12

p<0. 001 % ge with clinically significant reduction or increase in pain at 12 months p<0. 005 % ge with clinically significant reduction or increase in physical impairment at 12 months

Betty improves somewhat, but still complains of pain and fatigue. She is ready now

Betty improves somewhat, but still complains of pain and fatigue. She is ready now to accept the use of medications "What choices have I got ? "

μ opioid receptor agonist Has GABAergic, serotonergic and noradrenergic effects

μ opioid receptor agonist Has GABAergic, serotonergic and noradrenergic effects

Tramadol §Acts on opioid receptors in brain §Inhibits serotonin and norepinephrine reuptake, therefore interferes

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 Pain score in mm p < 0. 001<

Tramadol and Acetaminophen Effect on pain Pain score in mm p < 0. 001< T+A Placebo RM Bennett et al Am J Med 2003; 114: 537 -45

AMITRIPTYLINE CYCLOBENZAPRINE & FRIENDS

AMITRIPTYLINE CYCLOBENZAPRINE & FRIENDS

Placebo Cyclobenzaprine Cycl Amitriptyline Placebo Ami S Carette et al Arthritis Rheum 1994; 37:

Placebo Cyclobenzaprine Cycl Amitriptyline Placebo Ami S Carette et al Arthritis Rheum 1994; 37: 32 -40

Gabapentin and Pregabalin BLOCK Blockage of α 2δ subunit in Ca channel. Reduced release

Gabapentin and Pregabalin BLOCK Blockage of α 2δ subunit in Ca channel. Reduced release of glutamate, serotonin, noradrenalin, dopamine, substance P.

Pregabalin 13 weeks P A I N PJ Mease et al J Rheumatol 2008;

Pregabalin 13 weeks P A I N PJ Mease et al J Rheumatol 2008; 35: 502 -14

Patient global impression of change-PGIC Dropouts 33 -41%

Patient global impression of change-PGIC Dropouts 33 -41%

FIQ improved in 1 trial Pregabalin: Adverse Effects Dizziness Somnolence Headaches Weight gain Edema

FIQ improved in 1 trial Pregabalin: Adverse Effects Dizziness Somnolence Headaches Weight gain Edema

Duloxetine over 6 months Improvement in pain

Duloxetine over 6 months Improvement in pain

Duloxetine -Patient Global Improvement I J Russell et al Pain 2008; 136: 432 -44

Duloxetine -Patient Global Improvement I J Russell et al Pain 2008; 136: 432 -44

50 -55% of patients dropped out over 6 months Adverse effects : nausea, dry

50 -55% of patients dropped out over 6 months Adverse effects : nausea, dry mouth, constipation, insomnia

Other treatments • Electroacupuncture • Gabapentin • Pramipexole • Nabilone • Milnacipran ( not

Other treatments • Electroacupuncture • Gabapentin • Pramipexole • Nabilone • Milnacipran ( not available in Canada) • Raloxifen • Sodium oxybate • Fluoxetine (large doses)

No evidence for efficacy NSAIDs Narcotics All antidepressants not mentioned above Tender point injections

No evidence for efficacy NSAIDs Narcotics All antidepressants not mentioned above Tender point injections

Powered and controlled by team of health care professionals Drugs Aerobic Education exercise Srengthening

Powered and controlled by team of health care professionals Drugs Aerobic Education exercise Srengthening exercise CBT