session 6: fibromyalgia: dispelling myths, improving ... files/syllabus files...session 6:...

Session 6: Fibromyalgia: Dispelling Myths, Improving Management Learning Objectives • Dispel misinformation about fibromyalgia and rely on scientific evidence to explain its causes, recognize its

manifestations, and make an accurate diagnosis. • Analyze current pharmacologic and nonpharmacologic therapies for fibromyalgia to devise tailored, evidence-

based treatment plans. Faculty

Dr Philip J. Mease is a clinical rheumatologist and clinical professor of medicine. His research interests include pharmacotherapy of rheumatologic diseases and the methodology of disease assessment. He conducts clinical trials in emerging therapies for a number of conditions, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, fibromyalgia, systemic lupus erythematosus, osteoarthritis, and osteoporosis. Dr Mease has published extensively and is on the review boards of several rheumatic disease journals. He serves on the medical advisory boards of several pharmaceutical and biotechnology companies and foundations. He is a founding member of GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis), and chair/co-chair of 3 working groups of OMERACT (Outcome Measures in Rheumatology Clinical Trials). Dr Mease received his BA and MD degrees from Stanford University. He completed his residency in internal medicine at the University of Washington School of Medicine, where he was subsequently chief resident and fellow in rheumatology.

Philip J. Mease, MD Seattle Rheumatology Associates Chief of Rheumatology Research Swedish Hospital Medical Center Clinical Professor of Medicine University of Washington Seattle, Washington

Richard Harris, PhD Research Assistant Professor University of Michigan Ann Arbor, Michigan

Richard Harris is a research assistant professor in the Department of Anesthesiology at the University of Michigan. His background is in basic science and clinical research in alternative medicine. He received his BS degree in genetics from Purdue University in 1992 and his PhD in molecular and cellular biology from the University of California at Berkeley in 1997. Following his graduate work, he completed a postdoctoral fellowship at the National Institutes of Health, studying the rhythmic properties of neural cultures. He is a graduate of the Maryland Institute of Traditional Chinese Medicine and is currently investigating mechanisms of acupuncture in the treatment of chronic pain conditions. Faculty Financial Disclosure Statements The presenting faculty reported the following: Dr Mease receives grants for clinical research from Pfizer Inc.; Cypress; Forest Pharmaceuticals, Inc.; Eli Lilly and Company; Fralex; Boehringer-Ingelheim Pharmaceuticals, Inc.; and Allergan. He also receives grants for educational activities, and serves as an advisor or consultant to Pfizer Inc.; Cypress; Forest Pharmaceuticals, Inc.; Eli Lilly and Company; Fralex; Boehringer-Ingelheim Pharmaceuticals, Inc.; Allergan; and Jazz Pharmaceuticals. Dr Harris receives grants for clinical research and consultant fees from Pfizer Inc.

Session 6

Session 6

Education Partner Financial Disclosure Statement The content collaborators at MedIQ Research & Education have reported the following: Joyce Waskelo has nothing to disclose. Drug List Generic Trade carisoprodol Soma, Rela cyclobenzaprine Amrix, Flexeril duloxetine Cymbalta gabapentin Neurontin methocarbamol Delaxin, Forbaxin, Robaxin pregabalin Lyrica sodium oxybate Xyrem tizanidine Zanaflex, Sirdalud tramadol Ultram trazodone Desyrel zolpidem Ambien (es)zopiclone Lunesta Investigational milnacipran Suggested Reading List Abeles AM, Pillinger MH, Solitar BM, Abeles M. Narrative review: the pathophysiology of fibromyalgia. Ann Intern Med. 2007;146:726-734.

Arnold LM. Duloxetine and other antidepressants in the treatment of patients with fibromyalgia. Pain Med. 2007;8(suppl 2):S63-S74.

Bradley LA. Pathophysiologic mechanisms of fibromyalgia and its related disorders. J Clin Psychiatry. 2008;69(suppl 2):6-13.

Chakrabarty S, Zoorob R. Fibromyalgia. Am Fam Physician. 2007;76:247-254.

Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:1264-1273.

Glass JM. Fibromyalgia and cognition. J Clin Psychiatry. 2008;69(suppl 2):20-24.

Goldenberg DL. Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007;21:499-511.

Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA. 2004;292:2388-2395.

Leo RJ, Brooks VL. Clinical potential of milnacipran, a serotonin and norepinephrine reuptake inhibitor, in pain. Curr Opin Investig Drugs. 2006;7:637-642.

Mease P, Seymour K. Fibromyalgia syndrome update: emerging pharmacological treatments. J Musculoskel Med. 2007;24:436-445.

Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment. J Rheumatol. 2005;32(suppl 75):6-21.

Rooks DS. Talking to patients with fibromyalgia about physical activity and exercise. Curr Opin Rheumatol. 2008;20:208-212.

Staud R. Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome. Arthritis Res Ther. 2006;8:208.

Williams DA, Cary MA, Groner KH, et al. Improving physical function status in patients with fibromyalgia: a brief cognitive behavioral intervention. J Rheumatol. 2002;29:1280-1286.

Yunus MB. Role of central sensitization in symptoms beyond muscle pain, and the evaluation of a patient with widespread pain. Best Pract Res Clin Rheumatol. 2007;21:481-497.

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1

San Jose, CaliforniaNovember 19, 2008

2

Today’s ProgramA presentation of facts and evidence to dispel several common myths related to fibromyalgia...Part 1:• Overview of Fibromyalgia

– Epidemiology, disease classification, pathophysiology• Diagnosis

– Classic symptoms, clinical workup

Part 2:• Management of Fibromyalgia

– Treatment of pain and other symptom domains

3

Question• Have you ever given a patient the diagnosis

of fibromyalgia?1. Yes

2. No

?

Overview of Fibromyalgia

5

Question• How would you characterize fibromyalgia?

1. Autoimmune disease

2. Psychological disorder

3. Rheumatic or inflammatory disorder

4. Central nervous system disorder

5. Musculoskeletal disorder

?

6

Myth 1:

Fibromyalgia is not a real illness—it is psychological

2

7

Case Study Preview:Darlene’s Story

8

Fibromyalgia diagnosis is not based onexclusion of other disorders

Rheumatic disorders• Lupus (SLE)• Rheumatoid arthritis• Sjögren’s syndrome• Osteoarthritis

Infections and inflammation• Hepatitis C• Crohn’s disease• Lyme disease• Parvovirus infections

Fibromyalgia Often Associatedwith Other Disorders

Psychological disorders• Depression• Anxiety states• Posttraumatic stress disorder

(PTSD)

Other pain states• Irritable bowel syndrome• Pelvic pain syndromes• Sympathetic dystrophy• Neuropathies• Vascular headaches

9

What Causes Fibromyalgia?• Genetics

• “Triggers”

• Potential mechanisms1

– Central sensitization– Abnormalities of descending inhibitory pain pathways– Neurotransmitter abnormalities– Neurohumoral abnormalities– Psychiatric comorbid conditions

1. Abeles AM, et al. Ann Intern Med. 2007;146:726-734.10

Genetics of Fibromyalgia• Strong familial predisposition1

– >8 odds ratio for first-degree relatives

• Possible genetic polymorphisms:– 5-HT(2A) receptor2

– Serotonin transporter3

– Dopamine D4 receptor4

– COMT (catecholamine-O-methyl transferase)5

1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952.2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439.3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488.4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 5. Gursoy S, et al. Rheumatol Int. 2003;23:104-107.

11

Fibromyalgia “Triggers”• Peripheral pain syndromes

• Infections (eg, parvovirus, Epstein-Barr, Lyme disease)

• Physical trauma (eg, automobile accidents)

• Psychological stress/distress

• Hormonal alterations (eg, hypothyroidism)

• Certain catastrophic events (eg, war)

Clauw DJ, et al. Neuroimmunomodulation. 1997;4:134-153.McLean SA, et al. Med Hypotheses. 2004;63:653-658.

12

Pain Pathways

Facilitatory

Ascending• NMDA-glutamate• Substance P-NK-1• Nitric oxide

InhibitoryDescending• Norepinephrine• Serotonin• GABA• Opioids

– Endorphins– Enkephalins

Descending Pain Pathway

Thalamus

Hypothalamus

Processing Perception

of Pain

SpinalCord

DorsalHorn

Muscle Tissue(periphery)

Nociceptor

BrainStem

RapheNuclei

Cortex

Periaqueductalgray (PAG)

Ascending Pain Pathway

3

13

Central Sensitization: Enhanced Processing of Pain Stimuli• Amplified pain responses: abnormal “volume control”1

– Increased response to painful stimuli (hyperalgesia)– Pain from normally innocuous stimuli (allodynia)

• Scientific evidence:– Temporal summation of second pain (“wind-up”)– Increased activity on fMRI scans

• “Left-shift” in stimulus-response function– Elevated cerebral spinal fluid levels of neurotransmitters

(substance P, nerve growth factor)

1. Gracely RH, et al. Best Pract Res Clin Rheum. 2003;17:593-609.14

Temporal Summation:The Concept of “Wind-Up” Pain

Staud R. Arthritis Res Ther. 2006;8:208-214.

70

60

50

40

30

20

10

0T1 T5 T10 T15

Pain

Rat

ings

(0-1

00)

Mechanical Stimuli:Taps (T) to Adductor Pollicis Muscle of Hand

FM-3 secFM-5 secNC-3 secNC-5 sec

PainThreshold

15

Functional MRI: Objective Evidence of Augmented Pain Processing

Gracely RH, et al. Arthritis Rheum. 2002;46:1333-1343.

Stimulus Intensity (pressure applied to left thumb, kg/cm2)

Pain

Inte

nsity

14

12

10

8

6

4

2

01.5 2.5 3.5 4.5

FibromyalgiaSubjective Pain ControlStimulus Pressure Control

Arrows indicate significantincrease in fMRI signal

Left-shift in stimulus-response

16

Stimulus-Response Curve Shifts When Pressure-Induced Pain Is Reduced

SNRI = serotonin and norepinephrine reuptake inhibitor; in this trial, the investigative agent milnacipran.

Gracely RH, et al. Ann Rheum Dis. 2008;67(suppl II):255. Abstract.

• Placebo-controlled trial assessed effect of SNRI on pain-modulating systems in brain• Visual analog scale measured pain produced by repeated application of blunt pressure• At Week 12, a clinically relevant shift in stimulus-response for patients treated with SNRI

0 100 200 300 400 500 600 700 800 900 10000

10

20

30

40

50

60

70

VAS

(mm

)

Pressure (kPa)

PlaceboMilnacipran

fMRI of braindemonstrates

underlyingpathophysiology

In SNRI-treated patients,increased activity in

pain-modulating regions

17

0

10

20

30

40

50

ControlsFibromyalgia patients

1. Vaerøy H, et al. Pain. 1988;32:21-26.2. Russell IJ, et al. Arthritis Rheum. 1994;37:1593-1601.3. Liu Z, et al. Peptides. 2000;21:853-860.4. Bradley LA, et al. Arthritis Rheum. 1999;42:2731-2732.

Vaerøy1 Russell2 Liu3 Bradley4

fmol

/mL

Elevated CSF Levels of Pain Modulator (Substance P) in Fibromyalgia Patients

Diagnosis

4

19

Myth 2:

Fibromyalgia is a new and rare condition that affects

only middle-aged women

20

Nomenclature History

• Related monikers/syndromes:– Functional somatic syndromes

– Psychogenic rheumatism

– Chronic fatigue syndrome

– Gulf War syndrome

– Multiple chemical sensitivity syndrome

Muscular rheumatismNeurasthenia

Fibrositis Fibromyalgia

1981-Present1904-19811700-1904

21

Fibromyalgia Prevalence• 2% of general population in the US; about 5 million adults ≥18 years of age1,2

• 3.4% of female population2

– Female to male ratio 7:1

• All ages, from <10 years3 to elderly2

– Prevalence rises sharply in middle age, peaking at ages 70-79 years2

• 5%-6% of general practice patients4

• 10%-16% of rheumatology practice patients5

1. Lawrence RC, et al. Arthritis Rheum. 2007;58:26-35.2. Wolfe F. Arthritis Rheum. 1995;38:19-28.3. Eraso RM, et al. Clin Exp Rheumatol. 2007;25:639-644.4. Hartz A, et al. J Fam Pract. 1987;25:365-369.5. Neumann L. Curr Pain Headache Rep. 2003;7:362-368.

22

Identifying Fibromyalgia:ACR Classification Criteria• Chronic widespread musculoskeletal pain for ≥3 months

• Tenderness at ≥11 of 18 tender points– Detected by digital palpation of soft tissue with approximate

force of 4 kg/cm2

Wolfe F, et al. Arthritis Rheum. 1990;33:160-172.

• Sensitive (88.4%) and specific (81.1%) tool to differentiate fibromyalgia from other rheumatologic conditions

• Criteria need further refinement as knowledge about fibromyalgia evolves

23

Location of the Tender Points

Wolfe F, et al. Arthritis Rheum. 1990;33:160-172.

Anterior aspects of the C5,C7 intertransverse spaces

Second rib space – about 3 cmlateral to the sternal border

Medial fat pad of kneeproximal to joint line

Muscle attachments to lateral epicondyle

Insertionof nuchalmuscles into occiput

Upper border of trapezius,mid-portion

Upper outer quadrant of glutealmuscles

Muscle attachments just posterior to greater trochanter

Muscle attachmentsto uppermedial border of scapula

Practical use of examination:• Confirms diagnostic impression• Serves as proxy for pain sensitivity• Provides comparison with joint tenderness

24

Fatigue

Numbnessand tingling

Fibromyalgia: Constellation of Symptoms

Weakness

Irritablebowel/bladder

Depression/anxiety

Multiplechemical

sensitivity syndrome

Dysmenorrhea

Headache

Dizziness

Morningstiffness

Cognitivedysfunction

Sleepdisturbance

Widespreadpain with

tender points

5

25

Recommended Diagnostic Workup for Fibromyalgia

Adapted from Burckhardt C, et al. APS Clinical Practice Guideline Series, No.4; 2005. 25

Absence of other conditions that may present with chronic widespread pain

History of chronic, widespread pain for ≥3 months

Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18)

General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests)

Confirm diagnosis of fibromyalgia

Absence of other conditions that may present with chronic widespread pain

History of chronic, widespread pain for ≥3 months

Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18)

General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests)


26

Darlene’s Story:Diagnosis and Hope for Relief

27

Treatment options?

Initial Steps After Diagnosis

Adapted from Arnold LM. J Clin Psychiatry. 2008;69(suppl 2):14-19.

Identify important symptom domains and their severity (eg, pain, sleep disturbance, fatigue) and level of function

Evaluate for comorbid medical and psychiatric disorders(eg, sleep apnea, osteoarthritis, depressive or anxiety disorders)


Assess psychosocial stressors, level of fitness, and barriers to treatment

Provide education about fibromyalgia

May require referral to a specialist for full evaluation







28

Patient Education:Common Patient Questions• What is wrong with me?

• Why do I hurt all over?

• Why am I so exhausted?

• How did I get this?

• How is it treated?

• When will it go away?

• Why do people not believe me?

Goldenberg DL. J Clin Psychiatry. 2008;69(suppl 2):30-34.

29

Educating About Fibromyalgia:Increasing Patient Self-Efficacy• Consider group consultation

– Didactic talk with patient Q&A– More time-saving than one-on-one education

• Include core information – Explain pathophysiologic mechanisms (biopsychological model)– Dispel notion that absence of organic disease means symptoms

are psychogenic– Describe prognosis and clinical course– Reassure that fibromyalgia is not a prodrome of another disease– Emphasize that this condition can get better, but requires hard

work and self-management by the patient– Warn that media and Internet are often sources of misinformation

Goldenberg DL. J Clin Psychiatry. 2008;69(suppl 2):30-34.

Management of Fibromyalgia

6

31

Encourage exercise according to fitness level

Adjunctive cognitive-behavioral therapy for patients with prominent psychosocial stressors and/or difficulty coping and/or functioning

As first-line approach for patients with moderate-to-severe pain,trial with evidence-based medications

Review treatment options

Continuing the Stepwise Approach

Adapted from Arnold LM. J Clin Psychiatry. 2008;69(suppl 2):14-19.













Identify important symptom domains and their severity(eg, pain, sleep disturbance, fatigue) and level of function






32

Question• Which of the following nonpharmacologic therapies

has no evidence-based support for treatment of fibromyalgia?

1. Exercise regimen

2. Cognitive-behavioral therapy

3. Acupuncture

4. Hypnosis

5. Tender (trigger)-point injections

?

33

Nonpharmacologic Strategies: Evidence of Efficacy

Strong Evidence• Exercise

– Physical and psychological benefits– May increase tender point pain pressure

threshold and improve pain

• Cognitive-behavioral therapy– Improvement in pain, fatigue, mood, and

physical function often sustained for months

• Patient education/self-management– Improves pain, sleep, fatigue, and

quality of life

• Combination (multidisciplinary therapy)

Moderate Evidence• Strength training• Acupuncture• Hypnotherapy• EMG biofeedback• Balneotherapy (medicinal bathing)

Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Karper WB, et al. Rehabil Nurs. 2006;31:193-198; Busch AJ, et al. Cochrane Database Syst Rev. 2002; Mease P. J Rheum. 2005;75;6-21.

Weak Evidence• Chiropractic• Manual and massage therapy• Electrotherapy• Ultrasound

No Evidence• Tender-point injections• Flexibility exercise

34

Myth 3:

Fibromyalgia causes unavoidable, progressive

physical deterioration

35

Managing Deconditioning:Rationale for Aerobic Exercise

• Physical activity can increase fibromyalgia pain,leading to sedentary lifestyle

• Downward spiral of deconditioning can make symptoms worse at rest or with minimal exertion

Hoffman J, Jones KD. Understanding Fitness. 2008.

Pain

Lessmovement

Deconditioning/disuse syndrome Fear of

movement

Physical and mentaldeconditioning Fear of

injury

36

Aerobic Exercise Guidelines• Maximize tolerance and long-term compliance1

– Avoid high-intensity aerobic exercise (high dropout rates)

• Begin 1-2 months after start of drug therapy– Low-impact exercise, just below patient’s total capacity

– Gradually increase duration to goal of 30 minutes

1. Gowans SE, et al. Curr Opin Rheumatol. 2004;16:138-142.

7

37

Improvements AfterAerobic Fitness Training

Busch A, et al. Cochrane Database Syst Rev. 2002;2:CD003786.

-15-10

-505

101520253035

Exercise (n=379)Control (n=277)

*

*

AerobicPerformance

Mean Tender Point Pain Threshold Pain Intensity

% C

hang

e

*P<0.05.

38

Managing Psychological Distress:Cognitive-Behavioral Therapy (CBT)• Helps patients understand that fibromyalgia is

manageable and teaches adaptive skills, including:– Relaxation techniques – Goal setting– Problem solving– Self-reinforcement– Substituting maladaptive thoughts with positive thoughts

39

Improvements 1 YearAfter CBT Group Intervention

05

1015202530

PhysicalFunctioning

Sensory Pain Affective Pain

CBT Group Standard Care

*

*P<0.05.Williams DA, et al. J Rheumatol. 2002;29:1280-1286.

% C

hang

e

40

Managing Other Symptom DomainsSleep disturbance• Assess for primary sleep disorder; discuss sleep hygiene

• Minimize nocturnal pain and other sources of distress

• Recommend exercise at appropriate time of day

• Medications: TCA, short-acting hypnotic, muscle relaxant

Psychological distress• Mood-altering medications as appropriate

• Cognitive-behavioral therapy

• Psychiatric referral for selected patients

41

Question• What type of drug therapy would you initially

prescribe for a patient you’ve diagnosed with fibromyalgia?

1. Antidepressant

2. Antiepileptic

3. NSAID

4. Opioid analgesic

5. Sedative-hypnotic

?

42

Myth 4:

Fibromyalgia is best managed with NSAIDs for inflammation and

opioid analgesics for pain

8

43

Pharmacologic ApproachesClass Agents Randomized Controlled Trials

AntidepressantsSSRIs

Tricyclic antidepressantsSNRIs*

√√√

Antiepileptic Drugs GabapentinPregabalin*

√√

Analgesics NSAIDsTramadol/Opiates

√√

Muscle Relaxants

CyclobenzaprineTizanidine

CarisoprodolMethocarbamol

√

Sedative/Hypnotic

TrazodoneZolpidemZopiclone

Sodium oxybate

√√√

* The SNRI duloxetine and the AED pregabalin are the only FDA-approved agents for the treatment of fibromyalgia.

44

NSAIDs in Fibromyalgia• Nonsteroidal anti-inflammatory drugs constitute the number-one

class of agents used to treat fibromyalgia1

• No evidence of effectiveness as monotherapy for fibromyalgia– May be modestly helpful combined with a tricyclic

antidepressant2

• “Since fibromyalgia is not an inflammatory disease, it is not surprising we have a lot of treatment failures”3

• Chronic analgesic use can set up cycle of rebound headaches, complicating fibromyalgia management4

1. Clauw DJ. J Clin Rheumatol. 2007;13:102-109.2. Goldenberg DL, et al. Arthritis Rheum. 1986;29:1371-1377.3. Griffing GT. Medscape J Med. 2008;10(2):47.4. Chakrabarty S, Zoorob R. Am Fam Physician. 2007;76:247-254.

45

Opiates in Fibromyalgia• No adequate, randomized, controlled clinical trials1

• Opioids may heighten pain sensitivity (opioid-induced hyperalgesia)2

– Neuroadaptive changes lead to enhanced nociceptive output and decreased analgesic efficacy

• Tramadol (central-acting narcotic) has some opioid activity, combined with SNRI activity– May be efficacious, but is associated with nausea and dizziness3

– Better tolerated in fixed-dose combination with acetaminophen3

– Risk of seizures in patients using antidepressants, neuroleptics, or other drugs that decrease seizure threshold4

– Long-term addiction or abuse potential4

1. Clauw DJ. J Clin Rheumatol. 2007;13:102-109.2. Chu LF, et al. Clin J Pain. 2008;24:479-496.3. Bennett RM, et al. Am J Med. 2003;114:537-545.4. Goldenberg DL. Best Pract Res Clin Rheumatol. 2007;21:499-511. 46

Antiepileptics (Alpha-2-Delta Ligands):Pregabalin and Gabapentin• Mechanism:

– Bind to α2δ subunit of voltage-gated calcium channels– Reduce calcium influx and inhibit release of neurotransmitters (eg,

glutamate, substance P)

• Indications:– Postherpetic neuralgia (both agents)– Adjunctive therapy for partial onset seizures (both agents)– Pain associated with diabetic peripheral neuropathy (pregabalin)– Fibromyalgia (pregabalin)

Crofford LJ, et al. Arthritis Rheum. 2005;52:1264-1273.

47

Pregabalin: Improvement in Weekly Fibromyalgia Pain Scores

*For fibromyalgia indication, FDA-approved maximum dose is 450 mg/d.Arnold LM, et al. Presented at the Annual European League Against Rheumatism (EULAR) Congress,Barcelona, Spain; June 2007.

• Pooled analysis of 2 similarly designed randomized clinical trials (N=1493)• Monotherapy; 2 doses per day*• Statistically significant improvement with all pregabalin doses vs placebo

began at Week 1 and was sustained through endpoint

-3

-2

-1

0

1 2 3 4 5 6 7 8 9 10 11 12 13 EP

Treatment week

Cha

nge

From

Bas

elin

e in

LS

Mea

n Pa

in S

core

PlaceboPregabalin 300 mg/dPregabalin 450 mg/dPregabalin 600 mg/d

48

Pregabalin: Adverse Events

0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50%

Discontinuations*

Peripheral edema

Fatigue

Constipation

Dry mouth

Nausea

Vision blurred

Headache

Weight gain

Somnolence

Dizziness

600 mg/d450 mg/d300 mg/dPlacebo

* Due to all-cause AEs; among all pregabalin patients, dizziness (6.4%) and somnolence (4.0%) werethe AEs that most commonly led to discontinuation.Arnold LM, et al. Presented at the Annual European League Against Rheumatism (EULAR) Congress, Barcelona, Spain; June 2007.

9

49

Antidepressants for Fibromyalgia:Which To Choose?• Most studies using antidepressants as analgesics for fibromyalgia

demonstrate effects on pain that are distinct from effects on mood1

• Tricyclic antidepressants– Block reuptake of serotonin and/or norepinephrine– Low doses may effectively treat pain, poor sleep, fatigue2

– Tolerability issues; initiate therapy at very low doses, then titrate slowly1

• Selective serotonin reuptake inhibitors– Better side-effect profile than TCAs– Used at higher doses, the older, less-selective SSRIs are generally more efficacious

than “highly selective” agents1,3

• Dual receptor inhibitors– Inhibit both serotonin and norepinephrine– Unlike TCAs, generally no significant activity at other receptors; better tolerability1

– May have better analgesic effect than pure serotonergic drugs1

– Two SNRIs have undergone multicenter trials in fibromyalgia: duloxetine (FDA-approved therapy) and milnacipran

1. Clauw DJ. J Clin Rheumatol. 2007;13:102-109; 2. Arnold LM, et al. Psychosomatics.2000;41:104-113; 3. Fishbain D. Ann Med. 2000;32:305-316. 50

Duloxetine: Phase III Study • Male and female patients (N=520)

• Primary end points:– Brief Pain Inventory (average pain severity)– Patient Global Impression of Improvement

• Significant responses (secondary measures):– FIQ total score (only at 3 months)– CGI-S– SF-36 mental component – Certain MFI subscales

• Safety/tolerability similar to other clinical trials

FIQ = Fibromyalgia Impact Questionnaire; CGI-S = Clinical Global Impression-Severity Scale; SF-36 = SF-36 Health Survey Questionnaire; MFI = Multidimensional Fatigue Inventory.Russell IJ, et al. J Musculoskel Pain. 2007;15(suppl 13):58. Abstract 103.

51

% o

f Pat

ient

s

Effect of Duloxetine on AveragePain Score: ≥30% Improvement

Russell IJ, et al. J Musculoskel Pain. 2007;15(suppl 13):58. Abstract 103.

* †

*P≤0.05 vs placebo. †P≤0.01 vs placebo.

50.7 47.252.1 49.3

36.0 37.4

010

2030

40

50

60

3 Month 6 Month

Duloxetine 60 mg/dDuloxetine 120 mg/dPlacebo

52

Duloxetine Adverse Events: Pooled Phase III Studies (Female Subjects)

Adverse events reported in ≥5%.Arnold LM, et al. J Womens Health. 2007;16:1145-1156.

Placebo (n=212)n (%)

Duloxetine (n=326)n (%)

Nausea 26 (12.3) 114 (35.0)

Insomnia 31 (14.6) 79 (24.2)

Headache 28 (13.2) 70 (21.5)

Dry mouth 12 (5.7) 66 (20.2)Fatigue 20 (9.4) 54 (16.6)

Constipation 4 (1.9) 44 (13.5)

Dizziness 15 (7.1) 41 (12.6)Somnolence 6 (2.8) 26 (8.0)

Decreased appetite 2 (0.9) 23 (7.1)Increased sweating 2 (0.9) 19 (5.8)

Anorexia 1 (0.5) 18 (5.5)

53

Composite End Points

– Pain: 30% improvement recorded in electronic diary

– Global status: improvement on 7-point PGIC scale

– Function: SF-36 Health Survey, physical component summary

• Two trials (N=8881 and N=11962)– Milnacipran 100 or 200 mg/d

• Primary end points: composite analysis

Milnacipran for Treatment of Fibromyalgia: Phase III Trials

Milnacipran is not FDA-approved for the treatment of fibromyalgia.PGIC = Patient Global Impression of Change; FIQ = Fibromyalgia Impact Questionnaire.1. Clauw DJ, et al. Presented at the 2007 Annual Meeting of the American Society of Regional Anesthesia and Pain Medicine. Boca Raton, FL.2. Clauw DJ, et al. Arthritis Rheum. 2007;S306.

• Additional, secondary end points: – FIQ total score– Fatigue– Cognition

54

Milnacipran Outcomes: Composite Responder (Syndrome)

*P<0.05 vs placebo.†P<0.001 vs placebo.Clauw DJ, et al. Presented at the 2007 Annual Meeting of the American Society of Regional Anesthesia and Pain Medicine. Boca Raton, FL.

SyndromeEnd Points

33% 33%33% 32%

17% 19%

0

10

20

30

40

Milnacipran 100 mg/dMilnacipran 200 mg/dPlacebo

% o

f Pat

ient

s

3 Months 6 Months

* † *

10

55

Milnacipran Outcomes:Composite Responder (Pain)

Pain End Points

* † †*

% o

f Pat

ient

s

3 Months 6 Months

*P<0.05 vs placebo.†P<0.001 vs placebo.Clauw DJ, et al. Presented at the 2007 Annual Meeting of the American Society of Regional Anesthesia and Pain Medicine. Boca Raton, FL.

45% 44%45% 45%

27% 28%

01020304050

Milnacipran 100 mg/dMilnacipran 200 mg/dPlacebo

56

Milnacipran Phase III Extension Study:1-Year Maintenance of Pain Relief

Arnold LM, et al. Ann Rheum Dis. 2008;67(suppl II):249.

Lead-in study, 27 weeks (N=888); extension study, 28 weeks (N=449).Data represent continuing cohort of patients at each visit. VAS=24-hour recall of pain measured on 10-cm visual analog scale.

Lead-in: Milnacipran 200 mg/dayExtension: Milnacipran 200 mg/dayLead-in: Milnacipran 100 mg/dayExtension: Milnacipran 200 mg/day

% Im

prov

emen

t Pai

n VA

S

Week on Drug

Lead-In Extension

0

10

20

30

40

50

600 27 35 41 47 55

57

Milnacipran AEs: Pooled Data

AEs reported in ≥5% of patients, and at twice the incidence of placebo.*Less than twice the incidence of placebo. Clauw DJ, et al. Arthritis Rheum. 2007;S306.Clauw DJ, et al. Presented at the 2007 Annual Meeting of the American Society of Regional Anesthesia and Pain Medicine. Boca Raton, FL.

Placebo (n=624)%

Minacipran (n=1460)%

Nausea* 19.9 36.7Headache* 13.5 17.5

Constipation 3.5 15.9Hot flush 1.8 11.8Dizziness 5.1 10.3

Hyperhidrosis 1.6 8.6Palpitations 1.9 6.8

Vomiting 2.1 6.2Heart rate increased 1.0 5.8

Dry mouth 1.9 5.2

58

Summary of Findings:Studies in Fibromyalgia• TCAs display efficacy but are poorly tolerated

• SNRIs improve pain, other symptom domains, function, quality of life, and global well-being– Effect on pain independent of effect on mood– Duloxetine is FDA-approved for the treatment of fibromyalgia– Milnacipran NDA filing under FDA review

• Alpha-2-delta ligands show similar improvements and improve slow-wave sleep– Pregabalin is FDA-approved for the treatment of fibromyalgia

• Combination therapy may be an option for patients with:– Incomplete response to single agent– Poor tolerance to higher doses

Arnold LM. Arthritis Res Ther. 2006;8:212.

59

Darlene’s Story:Outlook on Life with Fibromyalgia

60

Summary: Practice Points• Fibromyalgia is a common pain syndrome characterized by:

– Widespread pain in peripheral tissues– Psychological distress– Central sensitization

• Pain component is consequence of disordered neurophysiology– Patients perceive more pain from nonpainful stimuli than do healthy

controls and experience greater pain from painful stimuli

• Rationale for treatment involves 3 important strategies:– Reduction of peripheral nociceptive input– Improvement or prevention of central sensitization– Treatment of pain-related negative affect

11

61

Summary: Practice Points (Cont’d)• Nonpharmacologic therapy includes:

– Aerobic exercise– Improved sleep– Cognitive behavioral therapy

• Pharmacologic therapy includes neuromodulatory agents:– TCAs, NRIs, dual reuptake inhibitors (SNRIs seem particularly

efficacious for FM pain)– Anti-epileptic medications (eg, pregabalin)

• For optimal disease management, treatment should be customized to address the symptom domains of each patient: pain, global sense of well being, and physical function

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