Muscle Pain Sally Kendall Parker InstituteSK 2004.

Muscle PainSally Kendall

Parker Institute SK 2004

Muscle pain

• 15% of adult population report chronic pain in the musculoskeletal system DIKE Danish Health and Morbidity Survey 1994

• 10% adult US population widespread pain, 20% chronic regional pain Wolfe et al J Rheumatology 1997

FM Prevalence: ”The end of the continuum?”

tenderness

%

2-4%

population

Clauw 2001

Fibromyalgia

•What is fibromyalgia?

•How do we diagnose fibromyalgia?

•What causes fibromyalgia?

•What is the frequency of FM?

•How can we treat FM?

What is fibromyalgia?

•Painful, non-articular condition involving muscles

•Widespread musculoskeletal pain

•Associated with fatigue, non-refreshing sleep

•May be part of a wider syndrome

Important symptoms in fibromyalgia

• Muscle pain

• Decreased endurance

• Fatigue and

• Poor sleep

• ”Exercise” intolerance

How do we diagnose fibromyalgia?

ACR-1990 Criteria: History of widespread pain

•Pain in both sides of the body

•Pain above and below the waist

•Axial skeletal pain

•Present for at least three months

Wolfe F. et al.Arthritis&Rheumatism, 1990

Digital palpation

Approximate force of 4 kg

A tenderpoint has to be painful

at palpation

not just ”tender”

ACR-1990

Fib.Reum.Klin.BDS

Pain in 11 of 18 tender points

• Suboccipital muscle insertions

• Anterior aspects of lig. intertransverse C5-C7

• Midpoint of the upper border of mm. Trapezius

• Supraspinatus at origins above the scapula

• Second rib - costochondrale junction

• 2 cm distal to the laterale epikondyles

• The upper outer quadrats of buttocks

• Posterior to the trochanteric prominence

• Mediale fat pad proximal to the joint line

What causes fibromyalgia?

Fibromyalgia is a syndrome!

• Predisposition

• Key events

• Mechanisms

Predisposition

• Polygenic predisposition + environment

Key events

• Infections• Physical trauma*• Psychological stress• Hormonal dysfunction• Drugs• Catastrophes*

• *Events perceived as stressful

Mechanisms

• Muscle Pain• Lund et al Scand J Rheumatol 2003 32 138-45

• Nørregaard et al Clin Physiol 1994 14 159-67

• Lund et al Scand J Rheumatol 1986 15 165-173

• Sensory processing

• Autonomic dysfunction• Backman et al Acta Neurol Scand 1988 77 187-91

• Neuroendocrine dysfunction • Væroy et al Pain 1988 21-26

• Russell et al Arthritis Rheum 1994 37:1593-601

Muscle Pain

Smerter-en lærebog 2003

From Smerte En Lærebog: Graven-Nielsen et al 1997

Referred pain

Sensory processing

• Interaction between ascending and descending pathways

• Evidence for abnormal central processing of noxious stimuli at cortical and sub-cortical levels leading to allodynia and hyperalgesia

•Mountz et al Arthritis Rheum 199538: 926-38•Lautenbacher & Rollman Clin J Pain 1997 13 189-96•Kosek et al Pain 1996 2-3 375-83•Bendtsen et al Arthritis Rheum 1997 40 98-102•Gracely et al Arthritis Rheum 2002 36: 1333-43

Allodynia

Hyperalgesia

Autonomic dysfunction

• Heart rate variability

• Impaired Stress response: noradrenaline and adrenaline

Petzke & Clauw Curr Rheumatol Rep 2000 2: 116-23 review

Neuroendocrine dysfunction

• Serotonin: low in blood• Substance P: CSF • Nerve growth factor: CSF • Dynorfin: CSF

• Probably NOT causes

What is the frequency of FM?

•Prevalence in the community: 1-3%

•Primary healthcare 2-6%

•Rheumatology practices up to 20%

•80-90% women

Prevalence: ”The end of the continuum?”

tenderness

%

2-4%

population

Clauw 2001

Age curve

FM och multi-symptomillnesses

• Overlap! FM 2-4%

Chronic Fatigue Syndrome 1%

multiple chemical sensitivity

exposure syndromes f.eks Gulf War syndrom, silicon breast implanter, sick building syndrome

Somatoform disorders 4%

Clauw 2001

Overlap!

• Chronic Fatigue Syndrome 21-80%• Irritabel Bowel Syndrome 32-80%• Temporomandibular Disorder 75%• Tension/Migraine Headache 10-80%• Multiple Chemical Sensitivities 33-55%• Interstitial Cystitis 13-21%• Chronic Pelvic Pain 18%

Aaron & Buchvald Best Practice & Res 2003 17: 563-74

Important symptoms in fibromyalgia patients: 2

• Depression1,2 2-34%

• Anxiety2 27%

1 Krag et al Acta Psychiatr Scand 1994 89 370-5

2.Epstein et al Psychomatics 1999 40 57-63

• Most experimental evidence against pain response bias by hypervigilance BUT psychological factors alter pain reporting and pain behaviour

Villemure & Bushnell Pain 2002 95: 195-9

Petzke et al J Rheumatol 2003 30:567-74

What treatment is available?

•Physical therapy

•Education and cognitive restructuring

•Multidisciplinary long-term treatment

•Myofascial therapy

•Aerobic exercise

•Drugs

Analgesia tAnalgesia targets

• Peripheral pain generators• Central pain processes

• Windup: an increase in pain sensation with time when given repetitive painful stimuli

• Temporal summation: the additive feeling of pain unpleasantness when painful stimuli continue

• NMDA receptor: important role in central sensitization

• DNIC: a system that sends inhibitory signals from the brain stem to the spinal cord => inhibits or filters out ascending pain signals

Rao Rheum Dis Clin NA 2003

The Dorsal Horn

• Paracetamol vs anti inflammatory drugsParacetamol vs anti inflammatory drugs

self-rated effectivenessself-rated effectiveness

0

5

10

15

20

25

30

35

40

45

%

muchworse

worse same better muchbetter

N=1042

Wolfe et al, Arthritis Rheum 2000 43: 378-385

Tramadol

• Rationale• opioid μ receptor binding + monoamine reuptake inhibition

• RCTRussell et al, A&R 1997 40:S117EffectiveBiasi et al, Int J Clin Pharm 1998 XV111 13-19 pain

• Clinical useBennett et al, Am J Med 2003 114:537-545Combination with paracetamol effective

Opioids

• Rationale

Act on ascending and descending pathways

• Fentanyl Staud et al Pain 2002 95:195-9 single

dose inhibits wind up

OpioidsOpioids

• Little FM data• Problems with side effects and addiction issues• Which aspects of pain processing and experience

are the target?

Fillingim Pain 2003 105: 385-6

Staud et al Pain 2002 95:195-9

Meta-analysis tricyclicsMeta-analysis tricyclics

• Rationale increase CNS concentrations by blocking 5-HT- and/or NA-mediated

neurotransmission, antihistamine and anticholinergic effects • 9 TCA studies

» 16 14 PBO controlled [5 insufficient data]

• Duration» 3-26 weeks [1 >12 weeks]

Arnold et al Psychosomatics 2000 41:104-113

Meta-analysis tricyclicsMeta-analysis tricyclics

• Sample size» 9-98 /group

• Effect size» Moderate overall» Best on sleep / less on pain

• Response» 35-37%

Fib.Reum.Klin.BDS

Comparison Between Fibromyalgia and Depression

Patients with FM had more tender points (16,5) than depressed patients (1,3)

Fassbender et al Clin Rheum 1997

SSRIsSSRIs

• Rationale 5-HT reuptake inhibition

• Fluoxetine Wolfe et al, Scan J Rheum, 1994 23:255-259

no efficacy cf PBO

Goldenberg et al, A&R 1996 39:1852-1859

Ami + Fluox improvements cf monotherapy/PBO

• Citalopram (most selective)

Norregaard et al, Pain 1995 61:445-449

No efficacy cf PBO

Anderberg et al, Eur J Pain 2000 4:27-35 depressive symptoms No other efficacy cf PBO

Pain transmission modulators:Pain transmission modulators:SSRIsSSRIs

• SertralineAlberts et al, A&R 1998 41:S259 pain threshold

Celiker et al ACR 2000

Ser 50mg/d compared to Ami 25mg/d

Both pain,fatigue,sleep disturbance,stiffness, tender point count

FluvoxamineNishikai et al, J Rheum 2003 30:1124-25

As effective as Ami pain

NA/5HT reuptake blockersNA/5HT reuptake blockers

• VenlaxafineDwight et al, Psychosomatics 1998, 39:14-17

6/11 improved 50% in 55%

small numbers, open study, max. tolerated dosage

Sayar et al J Psychosomatic Res 2003 55:147-8

Pain, function, depression, anxiety improved

small numbers, open study

Zijlstra et al Arthritis Rheum 2002 46: S105

RCT no effect (lower dosage)

• Reboxetin Browne & Chong 10th World Congresson Pain report 2002 Open label, 25 patients better pain and fatigue

Target:SleepTarget:Sleep

• ZopicloneDrewes et al, Scan J Rheum 1991,20:288-293

sleep better, pain + stiffness same

• ZolpidemMoldofsky et al, J Rheum 1996, 23:529-533

sleep better, pain + TePs + stiffness same

Side Effects

• Tramadol: • nausea, vomiting, CNS, pruritus, rash

• TCA: • urinretention, ileus, dry mouth

• SSRI: • nausea, vomiting,CNS, sexual dysfunction, hyponatremi, serotonergic

syndrome (hyperthermia + muscle spasmer +CNS/autonomic symptoms)

Future therapies?

• Gabapentin • Cation channel blocker, GABAergic transmission enhancer• role in FM? Case reports

• Pregabalin (anti eptileptic drug)

• Crofford et al, 2002 ACR S613• RCT dose-response 8wk trial

effective pain,fatigue,sleep disturbance,global assessment

• Milnacipran

• Gendreau et al, J of Pain 2003 4: Supp 1:80• NA+5-HT blockade + NMDA antagonism• Phase 11 trials published• Better pain, fatigue, mood

Future therapies?

• Rationale

• 5-HT3 antagonists

• Tropisetron Samborski et al Materia Medica Polona 1996 28: 17-9 19 in open trial pain and tenderness, vegetative symptoms

• Ondansetron Stratz et al Zeischrift fur Rheumatologie 1994 53: 335-8 crossover design pain and tenderness in 14/34

Future therapies?

• NMDA antagonists

• NK1 antagonists

• α2 agonists

• In the morning they asked her how she had slept. ”Dreadfully!” said the princess. ”I hardly got a wink of sleep all night! Goodness knows what can have been in the bed! There was something hard in it and now I´m just black and blue all over! It is really dreadful!”

……Only a real princess could be so tender as that.

The princess and the pea by

Hans Christian Andersen

Parker Instituttet