Fibromyalgia & Myofascial PainA Case for Central Sensitization

Joseph F. Audette MA, MDChief, Department of Pain Medicine

Harvard Vanguard Medical Associates

What is Fibromyalgia (FMS) ?Also called fibrositis ( 1900-1989 )Fibromyalgia (1990-)Common, affecting 2% of the US

populationWomen: 3.4% Men: 0.5% (Wolfe, 1995)

Children: 1.2% (Clark, 1998)

2nd most common musculoskeletal disorder seen by rheumatologists

1990 American College of Rheumatology Criteria

History of widespread pain: left, right, above and below the waist, axial painPresent for at least three monthsPain in 11 out of 18 anatomically

defined tender points when palpated with 4 kg/cm2 of force

Diagnosis of Inclusion

1990 Müller & Lautenschlager Criteria

Spontaneous pain in the musculature, in the course of tendons and insertions with typical locations near the spine and/or in the extremities, including the jaw region Longer than 3 months durationIn at least three different body regions

1990 Müller & Lautenschlager Criteria

Increased pressure sensitivity at 12 / 24 tender points with 2 kg/cm2 of forceAssociated autonomic and functional

symptoms (i.e.,sleep disturbances)Psychopathological findings including

neurosis, depression and anxietyNormal laboratory tests

Fibromyalgia and Costs to Society

In the States: 30% shorter work hours or less demanding work15% get some form of disability

paymentThe direct cost of FMS is in excess

of $16 billion annuallyWolfe F et al: Arthritis Rheum

1997;40:1560-1570

Causes of Widespread PainWhiplashMyofascial Pain SyndromeStatin drugsOpioid Induced HyperalgesiaHypothyroidismParasitic infectionsHepatitisOther rheumatic diseases

FibromyalgiaA fancy name for “chronic

widespread pain”

Patient with pain

Doctor, why do I have pain?

Pain is confirmed by tender points Dx: fibromyalgia

Because you have fibromyalgia

You have pain, because you have pain

Dommerholt J. J Musculoskeletal Pain 2000;8(4):41-47

Heim C, et al. Psychoneuroendocrinology. 2000;25:1-35.

Fibromyalgia & Stress Related Disorders

Hypocortisolism common to allDepressionPTSDPersian gulf syndromeInsomniaChronic fatigueChronic pelvic pain

MMPI and Somatoform Disorder

Copenhagen Declaration, 1993Patients with FMS should not be

treated as hypochondriacsPsychological distress is not a cause

for muscular pain and tendernessChronic Pain and tenderness is a cause

of psychological distress

Psychiatric Co-morbidityControlled studies using standard

psychologic instruments have concluded:No greater psychologic symptoms in

FMS patients than controlMajority of FMS patients do not have

an active psychiatric illnessNo evidence for a specific personality

type for FMS patientsHudson, Bailliere Clin Rheumatol, 1994

McBeth et al., Curr Rheumatol Rep, 2001

Kersh BC, Bradley LA, et al. Arthritis Rheum. 2001 Aug;45(4):362-71.

FMS Patient

Those FMS patients that visit a Rheumatology office did have a significantly higher psychiatric co-morbidity than did community FMS individuals.

Clauw DJ. J Musculoskel Med. 1999;Supplement:S7.

Tender PointsHigh tender point count may indicate:

More somatic symptoms

More severe fatigue

Low levels of self-care

Increased medical care usage

Higher level of distress

DEGREE OF FIBROMYALGIANESSWolf F. Ann Rheum Dis. 1997;56(4):268–71.

Who Gets Fibromyalgia?

Mostly women (9:1)20 to 60 years oldTypically has symptoms for 5 years

before diagnosisRheumatoid arthritis/lupusNo unique physical characteristicsAdolescents

Gender differences and painFemales more sensitive than males in all

sensory systems (Riley et al. Pain 1998; 74: 181-187.)

Most dramatic when tested with pressure pain threshold

Possible influence of sex hormones

Socio-cultural factors, including patient-doctor relationships

Psychophysical issues

Gender Differences and Chronic Pain

Serotonin synthesis fast7-fold drop in

serotonin synthesis after removal of tryptophanLow pain sensitivity

Serotonin synthesis slow42-fold drop in

serotonin synthesis after removal of tryptophanHigh pain sensitivity

Nishizawa S, Benkelfat C, Young SN et al: Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci USA,

1997;97:5308-5313

Males Females

Fibromyalgia

HeadachesDysmenorrhea

ChronicFatigue

Syndrome

Psychological Problems

Depression

Dyspareunia SinusitisPanic Disorder

RestlessLeg

Syndrome

InterstitialCystitis

IrritableBowel

Syndrome

Diagnosis of ExclusionRule out inflammatory arthritisDifferential diagnosis includes: myofascial

pain, hypothyroidism, hepatitis, nutritional disorders, somatoform disorder, depression, otherLaboratory tests are performed to exclude

mimics of FMS: CBC & LFTsESR to rule out an inflammatory disorder TSH, Vit D, B12, Fe levels

Lyme Disease

Differential Diagnosis

HypermobilitySyndrome

MetabolicDeficiencies

Geel SE. Seminars Arth Rheum. 1994;23(5):347.

The Evidence: Muscle Dysfunction in Fibromyalgia

Biopsy results (Bengtsson Arthritis Rheum. 1986;29:817.)Decrease in high energy phosphates

31P NMR spectroscopy of muscle (Jacobsen S, et al. J Rheumatol. 1992;19(10):1600-3)

No difference in phosphate energy stores compared to sedentary controls

Lack clear evidence to conclude there is a muscle abnormality

The Evidence: CNS Dysfunction in Fibromyalgia

Hyperalgesia & central sensitizationSerotonin deficiencyCSF elevation SP, NGFMuscle Biopsy shows elevated SP

(De Stefano J Rheumatol. 2000)

Russell IJ. J Musculoskel Med. 1999;Supplement:S13.

A Central Processing Problem?Comparison of nail bed pressure in

normals vs fibromyalgia patientsSame Stimulus in both groups caused

markedly different brain activation patternHigher Stimulus in normals to cause same

subjective pain levels as found with lower stimulus in fibro patients caused similar activation patterns in both groups

Supports the hypothesis that FM is characterized by cortical or subcortical augmentation of pain processing

Gracely, Arth Rheum, 2002

Evidence for Central Sensitization

Enhanced Temporal Summation with cutaneous thermal stimuli (Staud R, et al. Pain 2001;91:165.)

Heat probe at 51.5°C, 2 and 5s intervalsMechanical Allodynia found to

pressure < 4kg/cm2

IV Ketamine reverses Hyperalgesia and Lowers Pain Threshold over TP (Graven-Nielsen T, et. al. Pain 2000;85:483.)

NMDA Receptor and FMS

Abnormal CSF levels of SP, NGF, and 5HT suggest loss of descending inhibition on DH neurons Windup seen with temporal

summation dependent on NMDA activationResponse to Ketamine suggests

antagonism of NMDA receptor important to diminish pain associated with FMS

Opioid Hyperalgesia:NMDA Receptor Activation via PKCAntagonized by KetamineEvidence suggests PKC induction even

by brief intra-op exposureMay explain failure of preemptive

analgesia Opioid Hyperalgesia Found in methadone maintenance

patients (Doverty M, et al. Pain 2001;90(1-2):91.)

Believed to be linked to NMDA receptor activation

Opioids vs. KetamineNo RCT assessing oral opioids in

FMSDouble blind comparison of IV

Morphine (0.3mg/kg) Ketamine (0.3mg/kg) Lidocaine (5mg/kg) (Bengtsson SJ, et al. Scand J Rheum. 1995;24(6):360.)

Results

Morphine: no effect on pain intensity, pressure pain or exercise enduranceLidocaine: affected pain intensity

during and briefly after infusionKetamine: significantly improved all

three outcome measures

Medications for Fibromyalgia Syndrome

Tricyclic AntidepressantsAmitriptyline^^

Nortriptyline^^

Cyclobenzaprine ^

SSRIsFluoxetine 20-80 mg with orwithout tricyclic at bedtime ^

Sertraline 50 mg ^

SNRIsVenlafaxine 75 -225 mg/day^

Duloxetine 60 mg ^^*Milnacipran 50-100 mg BID^^*

Anti-convulsantsPregabalin 450 mg/d^^*Gabapentin 1200-2400 mg/d^

AnalgesicsTramadol 200-300 mg/d^^

^ Modest Evidence for Efficacy^^Strong Evidence for Efficacy

*FDA approved

Arnold LM, et al. J Pain. 2008 Jun 2.

Pregabalin and FibromyalgiaRCT of pregabalin 750 FMS patients assigned to

pregabalin (300 mg/d, 450 mg/d, 600 mg/d) or placebo, administered twice daily for 14 weeks.ResultsSignificant improvement in pain scores (P < .001: 300 mg/d, -0.71; 450 mg/d, -0.98; 600 mg/d, -1.00). Significant improvements in FIQ score: 450

mg/d (P = .004) and 600 mg/d (P = .003) All 3 doses of pregabalin were associated with

significant improvement in sleep

Arnold LM, et al. 1: Arthritis Rheum. 2007 56(4):1336-44.

Gabapentin and FibromyalgiaRCT compare gabapentin (1,200-2,400 mg/day)

(n=75 patients) with placebo (n=75 patients) for 12-week

Significant improvement in the BPI average pain severity score (P=0.015; estimated difference between groups at week 12=-0.92 [95% confidence interval -1.75, -0.71]).

Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale.

Low Dose Naltrexone31 woman with fibromyalgia in

RCT crossover study 2 week observation followed by

either placebo or 4.5 naltrexoneNaltrexone group had a more

significant reduction in pain (28% vs. 18%, P=0.016)Significant improvement in mood and satisfaction

with life (p<0.05)Younger J, et al. Arthritis & Rheum 2013;65(2):529–538

Myofascial Pain vs. Fibromyalgia

Is Fibromyalgia on one extreme of a continuum of central nervous system and muscle dysfunction that begins with more localized myofascial pain and can end with widespread pain if not appropriately diagnosed and treated?

Distribution of active trigger zones (n=100)

Regional 1-2 quadrants

55%

Widespread 3-4 quadrants

45%

Gerwin, R.. A study of 96 subjects examined both for fibromyalgia and myofascial pain (abstract). J Musculoskeletal Pain 1995 3: 121.

Myofascial vs. Fibromyalgia

Symptoms Fibromyalgia Myofascial Pain Pain Bilateral More Common Less Common Sleep Disturbance More Common Less Common Daytime Fatigue More Common Less Common Depression More Common Less Common Irritable Bowels More Common Less Common Urinary Frequency More Common Less Common Dysmenorrhea More Common Less Common Exercise Intolerance More Common Less Common Chronic Sinusitis More Common Less Common

Unique Characteristics of Muscle pain Aching, cramping pain, difficult to

localize and referred to deep somatic tissuesActivates unique cortical structures Inhibited more strongly by descending

pain-modulating pathwaysActivation of muscle nociceptors is

much more effective at inducing neuroplastic changes in dorsal horn neurons

Historical Considerations Samuel Solly, Esq., F.R.S. (1863) description

of Scriveners’ PalsyThe pain was a burning, uncomfortable feeling

between the knuckles... extending occasionally to the shoulder after writing about an hour...At times, the symptoms were very much more violent, and I frequently...had to put down my pen, feeling it quite impossible to continue work in that state....[Even after an extended rest] ...the burning sensation returned with great force, and extended all over the back part of my shoulder, and when I wrote I could feel it creeping down my side and under my shoulder-bone....accompanied by the old symptoms of burning and bursting..... it troubled me in the night, frequently keeping me awake for hours....

Cause of Underlying Pathology

Irritable Endplate TheoryPrimary Pathology in Muscle

Muscle Spindle DysfunctionPathology is Neuromuscular

Neuropathic TheoryPrimary pathology in CNS

Integrated Neuromuscular Theory

Travell, J.G., Simons, D.G., & Simons, L.S. (1999)Myofascial pain and dysfunction: The trigger point manual: Volume one, Upper half of body (2nd ed.)Baltimore, MD: Williams & Wilkins

Problems with Classic Irritable Endplate Theory

Latent Trigger Points: The Human ConditionWhat is different about a taut band in

someone with active pain at rest versus the majority of the adult population who has pain only on deep palpation

The Local Twitch Response

Audette JF, Wang F, et al. Am J Phys Med Rehabil. 2004 83(5):368-74.

Effect of Unilateral Dry Needling on an Active Trigger Point

Bilateral Twitch Response

Audette JF, et al. Am J Phys Med Rehabil. 2004 May;83(5):368-74.

Peripheral MechanismsMuscle nociceptors possess a

multitude of receptors for endogenous pain-producing and sensitizing agentsMuscle tenderness is mainly due to the

sensitization of muscle nociceptors by H+, PG’s, bradykinin and serotonin

Neurosecretory Properties of Unmyelinated Sensory Afferents

Convergence of Input to WDR Neuron

Dorsal Root Reflexes

Outflow on dorsal rootsInitial C-fiber

activityTissue-level peptide

releasePeng YB J Neurophysiol 2001

Dorsal Root Reflexes

Outflow on dorsal rootsInitial C-fiber

activityTissue-level peptide

releasePeng YB, J Neurophysiol 2001;86: 49-58.

Results of Joint Irritation on Muscle

Lowering of activation thresholds for muscle nociceptors with joint inflammationDevelopment of hyperalgesia &

Peripheral sensitizationGrigg P, Schaible,H, Schmidt R. Mechanical sensitivity of group III and IV afferents from posterior articular nerve in normal and inflamed cat knee. J Neurophysiology 55:635-643, 1986

Shah JP et al. J Appl Physiol. 2005 Nov;99(5):1977-84.

Microdialysis/Acupuncture Needle

Fluid in

Fluid outSolute exchange

surface – dialyzer membrane set 0.2 mm from the needle tip

Delivery tubes

Microdialysis/Acupuncture Needle

Chief Variables

Pain pressure threshold (PPT) -Fischer algometerlevels of pH, substance P,

calcitonin gene-related peptide (CGRP), bradykinin, norepinephrine, tumor necrosis factor α (TNF-α), and Interleukin -1 beta (IL-1β)

Measurement Active MTrPs compared to Latent MTrPs and toNormal Muscles

Pressure Pain Threshold (PPT)

P < 0.03

P < 0.08

pH

Substance P, CGRP

P < 0.01

Results

Bradykinin

Serotonin

Norepinephrine

Tumor Necrosis Factor (TNF-)

Interleukin (IL-1)

P < 0.01

P < 0.01

P < 0.01

P < 0.001

P < 0.001

Results

Substance P

0

50

100

150

200

250

300

350

400

0:00 2:24 4:48 7:12 9:36 12:00 14:24 16:48

Time

pg/m

l Gr.1Gr.2Gr.3

Substance P

CGRP

0

50

100

150

200

250

300

350

400

0:00 2:24 4:48 7:12 9:36 12:00 14:24 16:48

Time

pg/m

l Gr.1Gr.2Gr.3

CGRP

Goal of ExaminationFind the Cause of the Sensitized

SegmentJoint

Facet or SI jointShoulder or HipJaw

MuscleTraumaRepetitive StrainEmotional Holding Patterns

VisceraUterus, OvariesGallbladder

Myofascial Exam:Palpation, Palpation, Palpation!

Taut Band with Twitch response causing reproducible referral patternLoss of Range of MotionThermal PropertiesDermatographiaNon-Dermatomal Sensory LossWeakness without Neurologic

Findings Recognized Pain

Structural Assessment

Treatment: Trigger Point InjectionsNo high-quality, controlled trials

(Hong et al., Arch Phys Med Rehab 1996; Figuerola ML, et al. Funct Neurol 1998)Highly variable use by physiciansHighly variable response by patientsLidocaine, corticosteroid, botulinum,

“dry needling”Acupuncture & Fibro (Martin DP Mayo Clin Proc

2006;81:749-57)

Recent RCT supports use to reduce pain, anxiety, and fatigue

Treatment: Exercise

Exercise is routinely recommended – truly conventional

Conventional teaching – aerobic exercise at least 3 times a week

Referral to physical therapy common

Treatment: Exercise• Richards, 2002 – n=132; 35% vs. 18%

(aerobics. vs. relaxation); Improved on self assessment

• Jones, 2002 – n=62; strengthening vs. stretching 2x better in former

• Rooks, 2002 – n=15; CV & strengthening program well tolerated, compliance was 80%, improved from baseline

Rehab Options with Potentially More Lasting BenefitSelf Management TechniquesStretching and Strengthening with

relaxation/breathing methodsMeditationPostural Realignment/ PNF TechniquesPacingAerobic Conditioning

Joint Mobilization followed by above self management methods

Pharmacological InterventionsAcute PhaseHigh Dose NSAID’sOpioids? Steroids?Muscle Relaxant QHSCyclobenzaprine (Flexeril)Tizanidine (Zanaflex)

Pharmacological Interventions II

Acute Phase to Sub-Acute PhaseTCA in evening titrate to restorative

sleepReduce Central Facilitation

Consider Daytime Muscle Relaxant Tizanidine BaclofenClonazepam

Plus Minus NSAID’s

Combine with Manual Therapies

Goal to Diminish Afferent Drive and Facilitate Rehabilitation Process

Trigger Point InjectionsAcupunctureMassage TechniquesManipulative TherapiesJoint Injections

Pharmacological Interventions IIISub-Acute to ChronicAdd anticonvulsant -central facilitation

Gabapentin* (Neurontin 1800-4000 mg/day)Topiramate* (Topamax 100-600 mg/day)Levetiracetam* : (Keppra 500-3000, BID)Tiagabine* (Gabitril 2-24 mg/day)Zonisamide* (Zonegran 100-400 mg/day)Pregabalin* : (Lyrica 75 –600, TID)

If Depressed/Anxious Mood PredominantCalm Descending Drive from higher

CentersSSRI, SSNRI, Wellbutrin, AnxiolyticsBehavioral Psychology *Not approved by FDA for this use.

Multi-faceted Approach for Chronic Soft Tissue Pain

Spray/StretchStrain/counterstrainMuscle energyJoint Mobilization“Dry needling” - trigger

point acupunctureTrigger point injectionsMedicationsBotox injections

Orthotics, shoe modificationCounselingBehavioral

managementRelaxationImageryHypnosisCoping skillsAcupressure

Failure of Standard Treatment for Soft Tissue Pain

Failure to identify and eliminate underlying causeStructural UnderpinningsSystemic IllnessCause of Sensitized Segment

Psychological FactorsGenetic Predisposition

SummaryPresence of elevated levels of SP,

CGRP and cytokines suggests that soft tissue pain mediated by a process of central sensitization and neurogenic inflammationDetermining the biochemical profile of

active MTrPs may help elucidate mechanisms of the initiation and amplification of soft tissue pain and target treatments at those mechanisms