Fibromyalgia overview

Fibromyalgia: Disease Overview, Pathophysiology, and Clinical Features : 

Please see full prescribing information at this presentation. Fibromyalgia: Disease Overview, Pathophysiology, and Clinical Features

Overview: What Is Fibromyalgia? : 

Overview: What Is Fibromyalgia? FM is a common chronic widespread pain condition FM patients often have heightened sensitivity to pain (hyperalgesia); in addition, nonnoxious stimuli may result in pain (allodynia) Patients may present with a wide range of additional symptoms including tenderness, sleep disturbances, fatigue, morning stiffness, cognitive complaints, and mood disorders FM = fibromyalgia.Wolfe et al. Arthritis Rheum. 1995;38:19-28; Staud and Rodriguez. Nat Clin Pract Rheumatol. 2006;2:90-98; Wolfe et al. Arthritis Rheum. 1990;33:160-172; Henriksson. J Rehabil Med. 2003;(suppl 41):89-94.

Epidemiology of Fibromyalgia : 

Epidemiology of Fibromyalgia Prevalence FM is common worldwide and affects 2%-5% of US adult population Majority of patients between the ages of 35 and 60 years Gender differences Women are more likely to be diagnosed with FM than men Wolfe et al. Arthritis Rheum. 1995;38:19-28; Lawrence et al. Arthritis Rheum. 1998;41:778-799; Wolfe. Am J Med. 1986(suppl 3A);81:7-14; Weir et al. J Clin Rheumatol. 2006;12:124-128. Determining FM Prevalence FM prevalence in US is estimated to be 2%-5% Over 6 million Americans have FM US adult population FM is the most common chronic widespread pain condition

Pathophysiology of Fibromyalgia: Overview : 

Pathophysiology of Fibromyalgia: Overview Central pain mechanisms in FM CNS mechanisms (ie, central sensitization) may explain generalized heightened pain sensitivity of FM patients Increased levels of excitatory neurotransmitters (glutamate and substance P) may contribute to neuronal hyperactivity and central sensitization Compared with normal controls, CSF levels of substance P are 3-fold higher in patients with FM FM is believed to be a chronic, central pain state fMRI data provide supporting evidence that FM involves altered central pain processing fMRI = functional magnetic resonance imaging; CNS = central nervous system; CSF = cerebrospinal fluid.Staud and Rodriguez. Nat Clin Pract Rheumatol. 2006;2:90-98; Henriksson. J Rehabil Med. 2003;41(suppl 41):89-94; Gracely et al. Arthritis Rheum. 2002;46:1333-1343; Giesecke et al. Arthritis Rheum. 2004;50:613-623; Crofford and Clauw et al. Arthritis Rheum. 2002;46:1136-1138; Vaerøy et al. Pain. 1988;32:21-26; Russell et al. Arthritis Rheum. 1994;37:1593-1601. Despite extensive research, the pathogenesis of pain in FM is not clearly understood. However, central sensitization has emerged as a leading theory of disease mechanism.

Clinical Features and Diagnosis of Fibromyalgia : 

Please see full prescribing information at this presentation. Clinical Features and Diagnosis of Fibromyalgia

Clinical Features and Diagnosis of Fibromyalgia: Overview : 

Clinical Features and Diagnosis of Fibromyalgia: Overview Clinically, FM presents with chronic widespread pain in addition to a wide range of symptoms, including tenderness, sleep disturbances, fatigue, and morning stiffness Patients with FM are more likely to have comorbidities such as painful neuropathies and circulatory disorders ACR and Canadian criteria may be used to diagnose FM Symptoms may overlap with other conditions (IBS, MDD, CFS, SLE, RA, OA, Lyme disease); differentiation is essential for optimal management ACR = American College of Rheumatology; IBS = irritable bowel syndrome; MDD = major depressive disorder; CFS = chronic fatigue syndrome; SLE = systemic lupus erythematosus.Wolfe et al. Arthritis Rheum. 1995;38:19-28; Wolfe et al. Arthritis Rheum. 1990:33:160-172; Berger et al. Int J Clin Pract. 2007;61:1498-1508; Jain et al. J Musculoskelet Pain. 2003;11(4):3-107; Burckhardt et al. APS Clinical Practice Guideline Series, No.4.

Clinical Features of Fibromyalgia : 

TENDERNESS Presence of tender points Most patients also have tenderness to pressure, heat, cold, electrical pain SLEEP DISTURBANCES Characterized by nonrestorative sleep and increased awakenings Abnormalities in the continuity of sleep and sleep architecture Reduced slow-wave sleep Abnormal alpha wave intrusion in non-REM sleep WIDESPREAD PAIN Chronic, widespread pain is the defining feature of FM Patient descriptors of pain include: aching, exhausting, nagging, and hurting FATIGUE/STIFFNESS Morning stiffness and fatigue are common characteristics of FM Clinical Features of Fibromyalgia Wolfe et al. Arthritis Rheum. 1995;38:19-28; Leavitt et al. Arthritis Rheum. 1986;29:775-781; Wolfe et al. Arthritis Rheum. 1990:33:160-172; Roizenblatt et al. Arthritis Rheum. 2001;44:222-230; Harding. Am J Med Sci. 1998;315:367-376.

Fibromyalgia Is Often Associated With Sleep Disturbances : 

EEG = electroencephalogram.Roizenblatt et al. Arthritis Rheum. 2001;44:222-230; Harding. Am J Med Sci. 1998;315:367-376. Fibromyalgia Is Often Associated With Sleep Disturbances FM Patients Who Experienced Worsening of Pain After Sleep % of patients Phasic alpha Tonicalpha Lowalpha P<.001 Nonrestorative sleep is a prominent feature of FM FM patients report insomnia, early morning awakenings, and poor-quality sleep Alpha intrusion is a common but nonspecific EEG finding in FM patients May interfere with sleep function and contribute to worsening of pain after sleep Phasic, tonic, and low alpha are subtypes of alpha sleep intrusion observed in patients with FM

Rates of Mood Disorders in Fibromyalgia Are Similar to Other Rheumatologic Conditions : 

Rates of Mood Disorders in Fibromyalgia Are Similar to Other Rheumatologic Conditions Results of Structured Clinical Interview* *Mood disorders included major depressive episode, major depressive disorder, and dysthymic disorder.Thieme et al. Psychosom Med. 2004;66:837-844. 31 60 35 35 32 0 20 40 60 80 100 Mood disorder Anxiety % of patients

American College of Rheumatology (ACR) Criteria for FM : 

ACR criteria History of chronic widespread pain =3 months Patients must exhibit =11 of 18 tender points Widespread pain was found in 97% of patients with FM, compared with 70% in controls FM can be identified from among other rheumatologic conditions with use of ACR criteria Criteria need further refinement as knowledge about FM evolves American College of Rheumatology (ACR) Criteria for FM Wolfe et al. Arthritis Rheum. 1990:33:160-172. ACR criteria are both sensitive (88.4%) and specific (81.1%)

Canadian Diagnostic Criteria for FM : 

Canadian Diagnostic Criteria for FM Includes the ACR criteria and evaluates patients based on other symptoms commonly observed in FM (ie, sleep disturbance, fatigue) Chronic widespread pain and tenderness are core diagnostic features Clinical case definition of FM includes evaluation of additional clinical signs and symptoms commonly observed in patients with FM (neurocognitive manifestations, sleep disturbance, fatigue) Allows clinician to evaluate impact of entire clinical spectrum of FM and tailor treatment Jain et al. J Musculoskelet Pain. 2003;11(4):3-107; Mease. J Rheumatol Suppl. 2005;75:6-21; Wolfe et al. Arthritis Rheum. 1990:33:160-172.

Management of Fibromyalgia : 

Management of Fibromyalgia Please see full prescribing information at this presentation.

Management of Fibromyalgia (FM) : 

Management of Fibromyalgia (FM) Goldenberg et al. JAMA. 2004;292:2388-2395; Clauw et al. Best Prac Res Clin Rheumatol. 2003;17:685-701; Arnold et al. Arthritis Rheum. 2007;56:1336-1344. Nonpharmacologic Pharmacologic Aerobic exercise Cognitive behavioral therapy Patient education Strength training Acupuncture Biofeedback Balneotherapy Hypnotherapy Antidepressants Analgesics Anticonvulsants Until now there were no FDA-approved therapies for FM

Tricyclic Antidepressants (TCAs)*: Published Trials =8 Weeks Duration : 

AMI = amitriptyline; VAS = visual analog score; PBO = placebo; CBP = cyclobenzaprine; TP = tender points; NHP = Nottingham Health Profile; NTP = number of tender points; FIQ = Fibromyalgia Impact Questionnaire; VSGI = verbal scale global improvement; CGIC = clinician global impression of change; FDA = United States Food and Drug Administration.Carette et al. Arthritis Rheum. 1986;29:655-659; Carette et al. Arthritis Rheum. 1994;37:32-40; Ginsberg et al. J Musculoskelet Pain. 1996;4(3):37-47; Hannonen et al. Br J Rheumatol. 1998;37:1279-1286; Heymann et al. Clin Exp Rheumatol. 2001;19:697-702; Caruso et al. J Int Med Res. 1987;15:154-159; Bennett et al. Arthritis Rheum. 1988;31:1535-1542; Arnold LM. In: Wallace & Clauw’s Fibromyalgia and Other Central Pain Syndromes. Tricyclic Antidepressants (TCAs)*: Published Trials =8 Weeks Duration *No TCAs are currently FDA approved for FM.

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)*: Published Trials : 

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)*: Published Trials †Both publications are based on the same trial. BPI = Brief Pain Inventory; VAS = Visual Analog Score.Vitton et al. Hum Psychopharmacol Clin Exp. 2004;19:S27-S35; Gendreau et al. J Rheumatol. 2005;32:1975-1985; Arnold et al. Pain. 2005;119:5-15; Arnold et al. Arthritis Rheum. 2004;50:2974-2984; Dwight et al. Psychosom. 1998;39:14-17; Sayar et al. Ann Pharmacother. 2003; 37:1561-1565. *No SNRI is currently FDA approved for FM.

Analgesics*: Published Trials : 

Analgesics*: Published Trials †Doses of morphine equivalent per 24 hour were determined; ‡Single-dose cross-over trial with 1 week washout period.SF-36 = short-form 36; IV = intravenous; VAS = visual analog score.Bennett et al. Arthritis Rheum. 2005;53:519-527; Bennett et al. Am J Med. 2003;114:537-545; Kemple et al. Arthritis Rheum. 2003;48:S88; Russell et al. J Clin Rheumatol. 2000;6:250-257; Biasi et al. Int J Clin Pharmacol Res. 1998;18:13-19; Sorensen et al. Scand J Rheumatol. 1995;24:360-365. *No analgesic is currently FDA approved for FM.

Anticonvulsants*: Published Trials† : 

Anticonvulsants*: Published Trials† †Published either in peer-reviewed journals or studies included in the Lyrica® package insert. Includes open-label phase of trial. Arnold et al. APS, 2007; Crofford et al. APS, 2007; Crofford et al. Arthritis Rheum. 2005;52:1264-1273; Arnold et al. Arthritis Rheum. 2007;56:1336-1344. *Gabapentin is currently not FDA approved for FM.

Nonpharmacologic Therapies* : 

Nonpharmacologic Therapies* Patient education Intensive patient education in FM has been shown to improve pain, sleep, fatigue, and quality of life in patients with FM Aerobic exercise Exercise may increase aerobic performance and tender point pain pressure threshold, and improve pain Cognitive behavioral therapy (CBT) Some evidence of improvements in pain, fatigue, mood, and physical function *Only nonpharmacologic therapies with strong evidence are noted.Williams et al. J Rheumatol. 2002;29:1280-1286; Karper et al. Rehabil Nurs. 2006;31:193-198; Busch et al. Cochrane Database Syst Rev. 2002;CD003786; Goldenberg et al. JAMA. 2004;292:2388-2395.

Pregabalin: Mechanism of Action and Clinical Data : 

Pregabalin: Mechanism of Action and Clinical Data Please see full prescribing information at this presentation.

Pregabalin Binds to the a2-d Subunit of Voltage-Gated Ca2+ Channels in the Central Nervous System : 

Pregabalin Binds to the a2-d Subunit of Voltage-Gated Ca2+ Channels in the Central Nervous System Schematic representation of pregabalin’s proposed mechanism of action Pregabalin selectively binds to ?2-? subunit of voltage-gated calcium channels Modulates calcium influx in hyperexcited neurons Reduces neurotransmitter release (glutamate, substance P, norepinephrine) Pharmacologic effect requires binding at this site in animal models The clinical significance of these observations in humans is currently unknown Presynaptic a2-?subunit Ca2+ channel Neurotransmitters Postsynaptic Presynaptic a2-?subunit Ca2+ channel Neurotransmitters Postsynaptic Pregabalin Taylor. Epilepsy Res. 2007;73:137-150.

Low Potential for Pharmacokinetic Drug Interactions : 

Low Potential for Pharmacokinetic Drug Interactions Does not inhibit or induce major CYP450 enzymes No protein binding Pregabalin may exacerbate the impairment of cognitive and gross motor function when used in conjunction with oxycodone, lorazepam, and ethanol (alcohol) Patients who are taking other drugs associated with angioedema (ie, ACE inhibitors) may be at increased risk of developing angioedema *Derived from population pharmacokinetic analyses. ACE = Angiotensin Converting Enzyme. Lyrica® (pregabalin) Capsules Cv [package insert]. New York, NY: Pfizer Inc; 2007.

Pregabalin: Indications : 

Pregabalin: Indications Management of fibromyalgia Neuropathic pain associated with diabetic peripheral neuropathy (DPN) Post herpetic neuralgia (PHN) Adjunctive therapy for adult patients with partial onset seizures Lyrica® (pregabalin) Capsules Cv [package insert]. New York, NY: Pfizer Inc; 2007.

Pregabalin 14-Week Fixed-Dose FM Trial: Significant Improvement in Pain : 

† † Pregabalin 14-Week Fixed-Dose FM Trial: Significant Improvement in Pain †P<0.01; ‡P=.0125. *600 mg/day of pregabalin is not an approved dose for FM. End point mean pain score based on modified baseline observation carried forward approach (BOCF). Baseline mean = 6.7 (moderate to severe pain). P value–based LS means using MMRM ANCOVA. Scored 0-10, lower score represents improvement. Arnold et al. APS 2007; Data on file. Pfizer Inc, New York, NY. IMPROVEMENT LS mean change from baseline Week -3 -2 -1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 EP † † † † † † † † † † † † Placebo (n=184) Pregabalin 300 mg (n=183) Pregabalin 450 mg (n=190) Pregabalin 600 mg (n=188)* † † †

Most Frequent Adverse Events* by Dose in Controlled Trials of Pregabalin in FM (% of Patients) : 

*Those reported in =5% of all pregabalin-treated patients and twice the rate of placebo.†600 mg/d of pregabalin is not an approved dose for FM. Assessment of safety and tolerability was based on the 3 fixed-dose trials in FM. Lyrica® (pregabalin) Capsules Cv [package insert]. New York, NY: Pfizer Inc; 2007. Most Frequent Adverse Events* by Dose in Controlled Trials of Pregabalin in FM (% of Patients)

Pregabalin: Warnings and Precautions* : 

Angioedema Hypersensitivity Withdrawal from antiepileptic drugs Peripheral edema Dizziness and somnolence Weight gain Abrupt or rapid discontinuations Tumorigenic potential† Ophthalmologic effects Creatine kinase elevations Decreased platelet count PR interval prolongation *Please see prescribing information for comprehensive warning and precaution information. †Based on mouse-specific hemangiosarcoma. Lyrica® (pregabalin) Capsules Cv [package insert]. New York, NY: Pfizer Inc; 2007. Pregabalin: Warnings and Precautions*

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Capsules are available in 25, 50, 75, 100, 150, 200, 225, and 300 mg Pregabalin should be discontinued gradually over a minimum of 1 week Dosage adjustment is recommended for patients with reduced renal function (creatinine clearance =60 mL/min) and those undergoing hemodialysis A supplemental dose of pregabalin should be given following every 4-hour hemodialysis treatment There was evidence of dose-dependent adverse reactions Pregabalin in FM: Dosing and Administration Lyrica® (pregabalin) Capsules Cv [package insert]. New York, NY: Pfizer Inc; 2007.

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*Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose.†Supplementary dose is a single additional dose. TID = three divided doses; BID = two divided doses; QD = single daily dose Lyrica® (pregabalin) Capsules Cv [package insert]. New York, NY: Pfizer Inc; 2007. Pregabalin Dosage Adjustment Based on Renal Function