Fibromyalgia: What We Have Learned and How Treatment Is Evolving. Education Partner:

Transcription

1 Fibromyalgia: What We Have Learned and How Treatment Is Evolving Education Partner: St. Louis, Missouri November 13, 2008

2 Session 3: Fibromyalgia: What We Have Learned and How Treatment Is Evolving Learning Objectives Increase confidence in accurately diagnosing FM by accurately identifying at least 3 symptoms of FM and differentiating it from conditions with overlapping symptoms. List at least 3 of the benefits and adverse effects of current pharmacologic, nonpharmacologic, and combination therapies in the treatment of FM in order to select treatment that balances efficacy, safety, and tolerability. Faculty Edgar Ross, MD Director, Pain Management Center Brigham and Women s Hospital Pain Clinic Boston, Massachusetts Edgar L. Ross, MD, is director of the Pain Management Center at the Brigham and Women's Hospital in Boston, Massachusetts. Dr Ross, a nationally known expert in the field of pain management, has expertise in treating a wide variety of chronic pain types. His recent research interest is the treatment of angina with spinal cord stimulation. His interest and work in disease state management have resulted in several patents, some granted and some pending, in that specialty. Dr Ross has also published many articles and several book chapters on pain management, disease state management and the development of chronic pain management centers. Most recently, he published a book for primary care physicians on chronic pain, a subject of his many national and international lectures. Dr Ross has consulted for many organizations, including the Harvard School of Public Health, national network television stations, leading pharmaceutical firms, and medical consulting companies. Under his directorship, the Brigham and Women's Pain Center has become one of the largest and most respected academic pain centers in the country and has received recognition for conducting one the country s leading fellowship programs in chronic pain. With its large patient base as a foundation, the Brigham and Women s Pain Center has become an active and wellrespected clinical trials center. Kevin S. Ferentz, MD Associate Professor Department of Family Medicine University of Maryland School of Medicine Baltimore, Maryland Dr Kevin Ferentz is associate professor, Department of Family Medicine, University of Maryland School of Medicine, Baltimore, where he has also been residency director since Dr Ferentz received his MD degree from the State University of New York at Buffalo School of Medicine and completed his family practice residency at the University of Maryland. He then joined the faculty of the Department of Family Medicine at the University of Maryland He is a Diplomate of the National Board of Medical Examiners, Diplomate of the American Board of Family Practice, and a Certified Medical Reviewer Officer of the American Association of Medical Review Officers. Dr Ferentz has authored more than 2 dozen articles and book chapters on various issues in family medicine. He is the recipient of the Exemplary Teaching Award from the American Academy of Family Physicians. Dr Ferentz is a past-president of the Maryland Academy of Family Physicians and a member of the American Academy of Family Physicians, Society of Teachers of Family Medicine, and Association of Family Practice Residency Directors. He serves on the editorial boards of Medicine and Behavior and The Primary Care Companion to the Journal of Clinical Psychiatry. In addition, Dr Ferentz serves as reviewer for American Family Physician, Managed Care, and Family Medicine. Faculty Financial Disclosure Statements The presenting faculty reported the following: Dr Ross is on the speakers bureau and is a research consultant for Pfizer, Inc. Dr Ferentz is a consultant and is on the speakers bureau of Eli Lilly and Company. Education Partner Financial Disclosure Statements The content collaborators at Turnkey Solutions, LLC have reported the following: Emily A. Bakerman RN, MS, APN-C, executive vice president, has nothing to disclose. Session 3

3 Drug List Generic amitriptyline citalopram cyclobenzaprine duloxetine escitalopram fluoxetine gabapentin hydrocodone maprotiline Trade Elavil Celexa Flexeril Cymbalta Lexapro Prozac Neurontin various Ludiomil Generic methocarbamol naproxen pregabalin pramipexole tramadol venlafaxine Investigational milnacipran Trade Robaxin; component of Robaxisal various Lyrica Mirapex Ultram; component of Ultracet Effexor Ixel, Midalcipran Acronym List Acronym Definition Acronym Definition ACTH adrenocorticotropic hormone HPA axis hypothalamic pituitary adrenal axis CBT cognitive behavioral therapy IBS irritable bowel syndrome CFS chronic fatigue syndrome MCS multiple chemical sensitivity COMT catechol-o-methyl transferase OA osteoarthritis CRH corticotropin-releasing hormone PMR polymyalgia rheumatica CSF cerebrospinal fluid RA rheumatoid arthritis CTD connective tissue diseases RCT randomized controlled trial EBV Epstein Barr virus SNRI serotonin-norepinephrine reuptake FIQ Fibromyalgia Impact Questionnaire inhibitors FM fibromyalgia SSRI selective serotonin reuptake inhibitors fmri functional magnetic resonance imaging SLE systemic lupus erythematosus FMS fibromyalgia syndrome TCA tricyclic antidepressants FSS functional somatic syndromes TMJ temporomandibular joint disorder VAS Visual Analog Scale Suggested Reading List Arnold LM, Keck PE Jr, Welge JA. Antidepressant treatment of fibromyalgia: a meta-analysis and review. Psychosomatics. 2000;41(2): Arnold LM, Rosen A, Pritichett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119:5-15. Arnold LM. Biology and therapy of fibromyalgia. New therapies in fibromyalgia. Arthritis Res Ther. 2006;8:212. 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(4): Goldenberg DL. Pharmacological treatment of fibromyalgia. Best Pract Clin Rheumatol. 2007;21: Giesecke T, Williams DA, Harris RE, et al. Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum. 2003;48: Goldenberg DL. Pharmacological treatment of fibromyalgia. Best Pract Clin Rheumatol. 2007;21: Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain. Processing in fibromyalgia. Arthritis Rheum. 2002;46(5): Kroenke K. Efficacy of treatment for somatoform disorders: a review of randomized controlled trials. Psychosom Med. 2007;69: Kroenke K. The interface between physical and psychological symptoms. Prim Care Companion J Clin Psychiatry. 2003;(suppl 7): Kuchinad A. Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J Neurosci. 2007;27: Schulz R, Beach SR, Ives DG, et al. Association between depression and mortality in older adults. The Cardiovascular Health Study. Arch Intern Med. 2000;160: White KP, Nielson WR, Harth M, et al. Does the label fibromyalgia alter health status, function, and health service utilization? A prospective, within-group comparison in a community cohort of adults with chroinic widespread pain. Arthritis Rheum. 2002;47: Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33(2): Session 3

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5 Fibromyalgia: What We Have Learned and How Treatment is Evolving EDGAR ROSS, MD Director, Pain Management Center Brigham and Women s Hospital Pain Clinic Boston, MA Fibromyalgia (FM): Why So Much Controversy? Is it real? Is it physical or psychological? Can it be reliably diagnosed? Is a diagnosis helpful or harmful? Is there any effective treatment? Prevalence of Chronic Somatic Syndromes in the US Chronic Functional Illnesses Rheumatology Gastroenterology Neurology Infectious Disease Gynecology Cardiology Urology Allergy ENT Fibromyalgia Irritable bowel Tension headache Chronic fatigue Chronic pelvic pain Non-cardiac chest pain Irritable bladder Multiple chemical sensitivity Temporomandibular joint (TMJ) Wolfe et al. Scan J Rheum. 1994;23: ; Talley et al. Gastroenterology 1991;101: ; Wessely. Epidemiol Rev. 1995;17: ; Jason et al. Arch Int Med. 1999;159: Diagnosis dependent on: exclusion of disease, symptoms rather than signs, no reproducible laboratory findings Gold standard is expert opinion The Diagnosis of Fibromyalgia Chronic widespread musculoskeletal pain for > 3 months Absence of other systemic condition accounting for pain Multiple tender points at characteristic locations Characteristic features: Fatigue Headache Sleep disturbance Mood disturbance Parasthesias, swelling sensation Irritable bowel syndrome (IBS) Aaron et al. Arch Int Med. 2000;160: Diagnosis And Symptom Evaluation Initial Diagnosis Focused history: Chronic, widespread pain Musculoskeletal and tender point examination Selected laboratory testing Symptom activity, severity best measured by self-administered VAS Outcome best evaluated by FIQ and other composite functional scales No Moderate Worst pain pain possible pain Visual Analog Scale (VAS) 1 Goldenberg DL. Pharmacological treatment of fibromyalgia. Best Pract Clin Rheumatol. 2007;21:

6 Conditions Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle aches, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder Paradigm Shift in Fibromyalgia American College of Rheumatology criteria Chronic widespread pain Tenderness in >11/18 11/18 tender points Discrete illness Pain, focal areas of tenderness Psychological and behavioral factors nearly always present Anterior Posterior Newer Concept Part of a larger continuum Many somatic symptoms, diffuse tenderness Psychological and behavioral factors play roles in some individuals Who Gets Fibromyalgia? No concurrent medical illness 60-90% female in clinic, but < in population Any age, but peak age Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Who Currently Treats Fibromyalgia? More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists ACR suggest that rheumatologists serve as consultants (tertiary care) Other specialists should include mental health professionals, physiatrists, pain management experts and multidisciplinary ancillary support Earlier Diagnosis of Fibromyalgia Characteristic symptoms o I hurt all over o It feels like I always have the flu o Fatigue, Sleep and Mood disturbances o IBS, Irritable bladder, multiple other somatic complaints Rheumatic illness o Systemic CTD (RA, myositis, SLE, PMR) False + ANA pitfalls Seronegative spondyloarthropathies Exclusion of structural or systemic disease Not a fishing expedition Avoid screening rheumatology tests Most efficient with early subspecialty referral CTD=Connective Tissue Diseases. SLE= Systemic Lupus Erythematosus. PMR=Polymyalgia Rheumatica. FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression and anxiety Increased prevalence of mood disorders are primarily in tertiary-referral patients Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0) FM aggregates in families and co-aggregates with mood disorders. Odds of having FM in relatives is 8.5 in FM vs RA proband Arnold L et al. Family study of fibromyalgia. Arthritis Rheum. 2004;50:

7 Psychiatric Disorders in FM, FM Non-patients, Controls Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms Aaron LA. Arthritis Rheum. 1996;39: What Causes Fibromyalgia and Related Conditions? Genetics Significantly more common in families No single gene (COMT, 5-HTT haplotype) Triggers infection, physical, emotional trauma Pathophysiology Relationship between physiological and psychological factors Disordered sensory processing Autonomic/neuroendocrine dysfunction fmri Evidence of Central Sensitization in FM Pain intensity fmri = functional magnetic resonance imaging fmri Studies Show Cortical/Subcortical Augmentation of Pain Processing in FM Fibromyalgia 4 Subjective pain control Stimulus pressure control Stimulus intensity (kg/cm 2 ) Gracely et al. Arthritis Rheum. 2002;46: Accelerated Brain Gray Matter Loss in Fibromyalgia Patients: Premature Aging of the Brain? Neuroendocrine Changes in Fibromyalgia Alterations in CRH in FM. Abnormal pain sensitivity is of central origin HPA axis links pain, other stressors to endocrine, autonomic and behavioral responses. Interaction of pain neuropeptides (substance P) with serotonin, dopamine, noradrenaline. Environmental, genetic influences Brain gray matter, white matter, CSF, and total volume in 10 fibromyalgia patients and 10 healthy control subjects Kuchinad A et al. J Neurosci. 2007;27: CRH=Corticotropin-releasing Hormone. HPA axis=hypothalamic Pituitary Adrenal axis 3

8 Step-wise FM Therapy Primary Care Medications: Simple analgesics, low dose tricyclics* SSRIs*, SNRIs*, anticonvulsants* Education* Exercise*, low impact such as walking, water exercises If mood disturbances, treat with appropriate medications Tertiary Care Medications: tramadol*, combinations of antidepressants*, anticonvulsants, potent analgesics Cognitive behavioral program*, stress management therapy* Multidisciplinary pain management * Evidence of efficacy in controlled, clinical trials Goldenberg DL. Pharmacological treatment of fibromyalgia. Best Pract Clin Rheumatol. 2007;21: Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose mg Duration 6 26 weeks All showed modest efficacy Not FDA-approved for Fibromyalgia CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose mg Duration 4 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41: New Fibromyalgia Treatment Approaches Combination antidepressants (SSRI+TCA) Proportion of Responders Pregabalin in Fibromyalgia Individualized dosing (fluoxetine) Dual reuptake inhibitors (venlafaxine, duloxetine, milnacipran) Antiepileptics (gabepentin, pregabalin) Patient subsets treated differently Combine non-medicinal with drug therapies Proportion of Responders *P=0.003 vs Placebo * Multi-disciplinary programs Caution when combining multiple medications Pregabalin Dose (mg/day) Crofford L et al. Arth Rheum. 2005;52: Gabepentin: : Reduction on BPI Pain Severity Score * *p=0.014 N=150 Efficacy of Milnacipran, Duloxetine in FS RCTs ( mg/ day) (60 mg twice a day) p=0.027 % of Patients p=0.130 N=125 N=207 Not FDA-approved for Fibromyalgia Arnold LM, et al. Arthritis Rheum 2007;56: Gendreau, et al. J Rheumatol, 2005;32: Arnold LM et al. Arthritis Rheum. 2004;50: Not FDA-approved for Fibromyalgia 4

9 LS Mean Change from Baseline Duloxetine in FM: BPI Average Pain Severity Improvement Phase III Study: Female Patients (N=354) Weeks * * Not FDA-approved for Fibromyalgia Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *p<0.05 p vs placebo Arnold LM, et al. Pain 2005;119:5-15. Multidisciplinary FM Treatment Physical medicine/rehabilitation Avoiding inactivity Analgesic advice and non-pharmacologic treatment (MPS trigger point injections) Cardiovascular fitness Stretching, strengthening OT, work rehab, ergonomics Mental health professional Psychopharmacology Counseling CBT MPS=myofascial pain syndrome Exercise as it Relates to FM Moderate aerobic exercise (60-75% of age adjusted maximum heart rate ) {210-age}, at least 3X weekly Exercise should be slowly and carefully introduced Improvements in Aerobic Exercise vs Non-exercise Controls % Change * * Strength and stretching should be incorporated gradually Aerobic Performance *Statistically significant Mean Tender Point Pain Threshold Pain Intensity Busch A, et al. Exercise for treating fibromyalgia syndrome. Cochrane Database Syst Rev. 2002;(3):CD Group Illness Education Format Doctor, nurse, etc structured information Group format with spouse, family Open-ended questions at end Ideal for chronic illness like headaches, back pain, fibromyalgia, diabetes, obesity Learn from others, establish contacts Reimbursement a concern Does Fibromyalgia Label Alter Health Status? White, KP et al Arthritis Rheum 2002:47:

10 What is Typical Outcome in Fibromyalgia? Most patients have chronic, persistent symptoms Most patients continue to work, but 10-15% are disabled There is often adverse impact on work and leisure activities Duration of time without a diagnosis adversely affects outcome FM Subsets and Outcome Mode of Onset (a) infection (b) trauma Work setting Medicolegal setting Concurrent medical and psychiatric illness Levels of coping, catastrophizing Pharmacologic response Subgroups of FM Patients Group 1 (n=50) Low depression/anxiety Not very tender Low catastrophizing Moderate control over pain Group 2 (n=31) Tender High depression/anxiety Very high catastrophizing No control over pain Group 3 (n=16) Extremely tender Low depression/anxiety Very low catastrophizing High control over pain Psychological factors neutral Psychological factors worsening symptoms Psychological factors improving symptoms Giesecke et al. Arthritis Rheum. 2003;48: Primary Care Approach to Treating Patients KEVIN S FERENTZ, MD Associate Professor Department of Family Medicine University of Maryland School of Medicine Baltimore, Maryland Case 1 39 year old female Widespread muscle and joint pain for 10 years Poor sleep Bouts of anxiety and depression never treated Years of vague abdominal pain with alternating constipation and diarrhea Multiple food intolerances Wonders about multiple chemical sensitivities Pelvic pain and bladder irritability Evaluation Past Medical History: Chronic headaches since age 9 Treated as migraine and tension headaches Social history: Married; no children Accountant No history of sexual abuse Physical exam normal Labs ANA, ESR, RF, CBC normal X-rays of knees, back, hands - normal 6

11 TEST YOUR KNOWLEDGE Which of the following diagnoses is the patient least likely to have? 1. Fibromyalgia 2. Hypothyroidism 3. Irritable bowel syndrome 4. Somatization disorder 5. Major depression Symptom Syndrome Overlap? (Aaron & Buchwald studies) No. Studies Fibromyalgia 34 Irritable bowel syndrome (IBS) 21 Chronic fatigue syndrome (CFS) 18 TMJ syndrome 8 Migraine/tension headache 8 Multiple chemical sensitivity (MCS) 7 Aaron et al. Arch Int Med. 2000;160: Symptom Syndrome Overlap Overlap Fibromyalgia & CFS % Fibromyalgia & IBS % CFS & IBS % Fibromyalgia & MCS 33-55% CFS & MCS 30-67% TEST YOUR KNOWLEDGE Which of the following would be most helpful in distinguishing other Rheumatologic disorders from Fibromyalgia? 1. Fatigue and trouble sleeping 2. Tenderness only over the joints 3. Meets DSM-IV diagnostic criteria for major depression 4. Sleep disturbance 5. Normal X-rays? Aaron et al. Arch Int Med. 2000;160: Distinguishing Fibromyalgia from Other Rheumatologic Disorders Nonspecific somatic symptoms, particularly fatigue and sleep complaints, are common in multiple rheumatologic and pain conditions Depressive and anxiety disorders are also prevalent in many rheumatologic conditions Laboratory tests (e.g., elevated ESR or X-ray findings) are generally discriminatory only if they are abnormal The tender points seen with fibromyalgia are not limited to the joints but are on right and left sides of body, upper and lower, proximal and axial. Assessing Fibromyalgia The American College of Rheumatology Criteria for the Classification of Fibromyalgia History of widespread pain has been present for at least three months Pain is considered widespread when all of the following are present: Pain in both sides of the body Pain above and below the waist Pain in 11 of 18 tender point sites on digital palpation (she has 14/18 tender points) Wolfe F, et.al. Arthritis Rheum. 1990;33(2):

12 TEST YOUR KNOWLEDGE Which symptom would be most helpful in diagnosing comorbid depression? 1. Fatigue 2. Trouble concentrating 3. Sleep complaints 4. Loss of interest (anhedonia) 5. Multiple pain complaints? SPACE DIGS [9 DSM-IV Symptoms of Depression] S leep P sychomotor A ppetite C oncentration E nergy D epressed I nterest G uilt S uicidal more depression- specific Kroenke K. Ann Intern Med. 1997;126: PHQ-4 Over the last 2 weeks, how often have you been bothered by the following problems? Feeling nervous, anxious, or on edge Not at all (0) Several days (1) More than half the days (2) Nearly every day (3) Fibromyalgia: Overlap with Depression and Anxiety Disorders p<0.001 Not being able to stop or control worrying Little interest or pleasure in doing things p=.013 Feeling down, depressed, or hopeless Items 1 & 2 screen for anxiety; items 3 & 4 for depression Score 3 on either two-item screen is positive screen Kroenke et al, Psychosomatics, in press. n =228 n =108 Arnold LM, et al. J Clin Psychiatry Aug;67(8): Prevalence of Pain Symptoms by Severity of Depression in 3000 Medical Outpatients Type of Pain Case 2 52 year old male Presents with chronic neck pain, headache, sleep and mood disturbances Has been out of work for 5 years Past Medical History: - Chronic back pain x 20 yrs - Back surgery 5 years previous (HNP) - Multiple courses of physical therapy and injections for pain Physical Exam: Normal, except widespread tenderness Laboratory findings: Within Normal Limits MRI of back: degenerative disc disease, no cord or spinal nerve compression Kroenke K. Primary Care Companion. J Clin Psychiatry. 2003;(suppl 7):

13 TEST YOUR KNOWLEDGE What would you prescribe to treat the fibromyalgia component of this man s illness? 1. Naproxen 2. Acetaminophen 3. Escitalopram 4. Amitriptyline 5. Methacarbamol? Treatment of Fibromyalgia with Antidepressants: A Meta-analysis analysis O'Malley PG et al. J Gen Intern Med. 2000;15: TEST YOUR KNOWLEDGE The patient does not tolerate the tricyclic antidepressant, and fails to improve with a trial of cyclobenzaprine. All of the following are reasonable medications to try next EXCEPT 1. Tramadol 2. Hydrocodone 3. Pregabalin 4. Duloxetine 5. Gabapentin? TEST YOUR KNOWLEDGE The patient partly improves with combined medications. He is not interested in a regular exercise program. The most evidence-based nonpharmacologic treatment to add at this point is: 1. Physical therapy 2. Interpersonal psychotherapy 3. Cognitive-behavioral therapy 4. Acupuncture 5. TENS unit? Cognitive-Behavioral Therapy (CBT) CBT effective in fibromyalgia 4 of 6 trials involving 596 patients 1 CBT effective in functional somatic syndromes (FSS) 20/28 trials, including back pain (3/5), IBS (3/3), chronic fatigue syndrome (2/3), noncardiac chest pain (2/3), and FSS (7/11) 2 CBT effective in somatoform disorders and unexplained symptoms 11/13 trials 3 Therapies with No to Mixed Evidence in Fibromyalgia No Evidence NSAIDs Corticosteroids Opiates Chiropractic Trigger or tender point injections TENS units Mixed Evidence SSRIs Acupuncture Massage Strength exercises Hypnosis Biofeedback Balneotherapy 1. Kurtais, Kutlay & Ergin. Curr Pharmaceutical Design 2006;12: Kroenke & Swindle, Psychother Psychosom 2000;69: Kroenke K, Psychosom Med 2007;69: Goldenberg DL, et al. JAMA 2004;292: Rooks DR. Curr Opin Rheumatol 2007;19:

14 Stepwise Treatment of Fibromyalgia Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Review treatment options Confirm diagnosis Identify important symptom domains, their severity, and level of patient function Evaluate for comorbid medical and psychiatric disorders May require referral to a specialist for full evaluation This information concerns a use that has not been approved by the US Food and Drug Administration. Stepwise Treatment of Fibromyalgia (cont) As a first-line approach for patients with moderate to severe pain, trial with evidence-based medications Provide additional treatment for comorbid conditions Adjunctive CBT for patients with prominent psychosocial stressors, and/or difficulty coping, and/or difficulty functioning Encourage exercise according to fitness level This information concerns a use that has not been approved by the US Food and Drug Administration. Arnold LM. Arthritis Res Ther 2006;8:212. Arnold LM. Arthritis Res Ther 2006;8:212. Take Home Message FM is common and affects 2 5% of the population Majority of patients between years Women more likely to be diagnosed then men Patients 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 Fibromyalgia: What We Have Learned and How Treatment is Evolving EDGAR ROSS, MD KEVIN S FERENTZ, MD 10