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Development Committee

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Presentation on theme: "Development Committee"— Presentation transcript:

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2 Development Committee
Mario H. Cardiel, MD, MSc Rheumatologist Morelia, Mexico Andrei Danilov, MD, DSc Neurologist Moscow, Russia Smail Daoudi, MD Tizi Ouzou, Algeria João Batista S. Garcia, MD, PhD Anesthesiologist São Luis, Brazil Yuzhou Guan, MD Beijing, China Jianhao Lin, MD Orthopedist Beijing, China Supranee Niruthisard, MD Anesthesiologist, Pain Specialist Bangkok, Thailand Germán Ochoa, MD Orthopedist, Spine Surgeon and Pain Specialist Bogotá, Colombia Milton Raff, MD, BSc Consultant Anesthetist Cape Town, South Africa Raymond L. Rosales, MD, PhD Neurologist Manila, Philippines Ammar Salti, MD Consultant Anesthetist Abu Dhabi, United Arab Emirates Jose Antonio San Juan, MD Orthopedic Surgeon Cebu City, Philippines Xinping Tian, MD Rheumatologist Beijing, China Işin Ünal-Çevik, MD, PhD Neurologist, Neuroscientist and Pain Specialist Ankara, Turkey Speaker’s Notes Please acknowledge the members of the development committee. This program was sponsored by Pfizer Inc.

3 Learning Objectives After completing this module, participants will be able to: Discuss the prevalence of various syndromes involving central sensitization/dysfunctional pain, focusing on fibromyalgia Understand the impact of syndromes involving central sensitization/dysfunctional pain, such as fibromyalgia, on patient functioning and quality of life Explain the pathophysiology of central sensitization/ dysfunctional pain Recognize core clinical features of fibromyalgia Select appropriate pharmacological and non-pharmacological strategies for the management of fibromyalgia Speaker’s Notes Review the learning objectives for this session. Ask the participants if they have any additional goals.

4 Table of Contents What is central sensitization/dysfunctional pain?
How common is central sensitization/ dysfunctional pain? What are the clinical features of syndromes involving central sensitization/dysfunctional pain, such as fibromyalgia? How should syndromes involving central sensitization/dysfunctional pain, such as fibromyalgia, be treated based on their pathophysiology? Speaker’s Notes This slide outlines the overall flow of the presentation.

5 Pathophysiological Classification of Pain
Central sensitization/ dysfunctional pain Multiple pain mechanisms may coexist (mixed pain) Nociceptive pain Somatic Visceral Neuropathic pain Peripheral Central Speaker’s Notes This slide illustrates three broad categories of pain: central sensitization/dysfunctional, neuropathic and nociceptive pain. It should also be noted that many conditions feature more than one type of pain, and are thus termed ‘mixed pain’ states. Nociceptive pain is an appropriate physiologic response that occurs when specific peripheral sensory neurons (nociceptors) respond to noxious stimuli. Nociceptive pain has a protective role because it elicits reflex and behavioral responses that keep tissue damage to a minimum. Nociceptive pain may be somatic or visceral in origin. Somatic pain, such as gout, osteoarthritis and trauma-induced pain, originates with the musculoskeletal or cutaneous nociceptors and is often well localized. Visceral pain, such as dysmenorrhea or acute pancreatitis, originates in nociceptors located in the hollow organs and smooth muscles; it is often referred. Neuropathic pain has been defined by the International Association for the Study of Pain as “Pain caused by a lesion or disease of the somatosensory nervous system.” Depending on where the lesion or dysfunction occurs within the somatosensory nervous system, neuropathic pain can be peripheral in origin (as in painful diabetic peripheral neuropathy and postherpetic neuralgia) or central in origin (for example, neuropathic pain associated with stroke or spinal cord injury). Central sensitization/dysfunctional pain is defined as “Hypersensitivity of the pain system such that normally innocuous inputs can activate and perceptual responses to noxious inputs are exaggerated, prolonged and spread widely”. Some common examples for this pain type are: fibromyalgia, temporomandibular joint disorder, chronic migraine/tension type headache, interstitial cystitis, irritable bowel syndrome and complex regional pain syndrome. There are cases in which more than one type of pain pathophysiology exist (mixed pain). For example, in a lumbar herniated disc patient with radiculopathy, it is common to experience both nociceptive/inflammatory pain, felt around the low back area with movement, and neuropathic pain, felt in the distribution territory of the effected root (lower extremity). Note that Woolf (2011) defines central sensitization as amplification of neural signaling within the CNS that elicits pain hypersensitivity. References Freynhagen R, Baron R. The evaluation of neuropathic components in low back pain. Curr Pain Headache Rep 2009; 13(3): Jensen TS et al. A new definition of neuropathic pain. Pain 2011; 152(10): Julius D et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006. Ross E. Moving towards rational pharmacological management of pain with an improved classification system of pain. Expert Opin Pharmacother 2001; 2(1): Webster LR. Breakthrough pain in the management of chronic persistent pain syndromes. Am J Manag Care 2008; 14(5 Suppl 1):S Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152(3 Suppl):S2-15. Freynhagen R, Baron R. Curr Pain Headache Rep 2009; 13(3):185-90; Jensen TS et al. Pain 2011; 152(10):2204-5; Julius D et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Ross E. Expert Opin Pharmacother 2001; 2(1): ; Webster LR. Am J Manag Care 2008; 14(5 Suppl 1):S116-22; Woolf CJ. Pain 2011; 152(3 Suppl):S2-15.

6 Why do patients suffering from central sensitization experience dysfunctional pain?
During central sensitization, the sensation of pain is enhanced as a result of: Changes in nerve fibers and the environment Modifications of the functional properties and the genetic programming of primary and secondary afferent neurons Speaker’s Notes Unrelieved pain may trigger changes in the neural structure involved in in the transmission and modulation of pain, leading to the development of chronic pain. However, the exact mechanisms involved in these processes are not well understood. Reference Fornasari D. Pain mechanisms in patients with chronic pain. Clin Drug Investig 2012; 32(Suppl 1):45-52. Fornasari D. Clin Drug Investig 2012; 32(Suppl 1):45-52.

7 What is central sensitization/ dysfunctional pain?
Definition Amplification of neural signaling within the CNS that elicits pain hypersensitivity Examples Fibromyalgia Tension-type headache Irritable bowel syndrome Interstitial cystitis Temporomandibular joint pain May be present in many patients with chronic low back pain, osteoarthritis and rheumatoid arthritis Pain Quality Often diffuse Frequently with allodynia and/or hyperalgesia Rarely burning, lancinating or electric shock-like Speaker’s Notes One definition of central sensitization/dysfunctional pain is “hypersensitivity of the pain system such that normally innocuous inputs can activate and perceptual responses to noxious inputs are exaggerated, prolonged and spread widely”. Some examples of this type of pain are fibromyalgia, temporomandibular joint disorder, chronic migraine/tension-type headache, interstitial cystitis, irritable bowel syndrome and complex regional pain syndrome. Patients with these conditions experience pain hypersensitivity, after-sensations and enhanced temporal summation, and frequently display comorbid symptoms such as fatigue, sleep disturbance and/or mood disorders. These common features suggest a common pathophysiology for this type of pain, the terminology for which is in flux. Reference Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011; 152(3 Suppl):S2-15. CNS = central nervous system Woolf CJ. Pain 2011; 152(3 Suppl):S2-15.

8 Clinical Features of Central Sensitization/Dysfunctional Pain
Pain all over body Muscles stiff/achy Headaches Pain in jaw Pelvic pain Bladder/urination pain Anxiety/depression Sad or depressed Anxiety Stress makes symptoms worse Tension in neck and shoulder Grind/clench teeth Fatigue Do not sleep well Unrefreshed in morning Easily tired with physical activity Other symptoms Difficulty concentrating Need help with daily activities Sensitive to bright lights Skin problems Diarrhea/constipation Speaker’s Notes A growing body of evidence is demonstrating that central sensitization/dysfunctional pain represents a common pathophysiological mechanism for the overlapping clinical features of central sensitivity syndrome such as fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome and temporomandibular disorder. Within this emerging model, one can view symptoms of central sensitization/dysfunctional pain not as individual disorders, but as different manifestations of a common etiology. This slide shows how clinical features of central sensitization/dysfunctional pain can be categorized as “pain,” “anxiety/depression,” “fatigue,” and “other symptoms.” Reference Mayer TG et al. The development and psychometric validation of the central sensitization inventory. Pain Pract 2012; 12(4): Mayer TG et al. Pain Pract 2012; 12(4):

9 how often do you see patients with these clinical features?
Discussion Question how often do you see patients with these clinical features? Speaker’s Notes Ask the question shown on the slide to participants to stimulate discussion.

10 How common is central sensitization/ dysfunctional pain?
~40% of adults suffer from chronic pain1 17–35% of chronic pain patients suffer from generalized hypersensitivity and conditioned pain modulation2 Speaker’s Notes Central sensitization/dysfunctional pain is quite common. It has been estimated that approximately 40% of adults worldwide suffer from chronic pain.1 Of these chronic pain suffers, 17–35% suffer from generalized hypersensitivity and conditioned pain modulation.2 Overall, the estimated prevalence of central sensitization/ dysfunctional pain among adults is estimated to range from 5–15%. References Tsang A et al. Common chronic pain conditions in developed and developing countries: gender and age differences and comorbidity with depression-anxiety disorders. J Pain 2008; 9(1): Schliessbach J et al. The prevalence of widespread central hypersensitivity in chronic pain patients. Eur J Pain 2013; 17(10): 1. Tsang A et al. J Pain 2006; 9(10):883-91; 2. Schliessbach J et al. Eur J Pain 2013; 17(10):

11 Common Diagnoses Among Patients Suffering from Central Sensitization/Dysfunctional Pain
Speaker's Notes Medically indistinct (or non-specific) disorders, such as fibromyalgia, chronic fatigue syndrome and irritable bowel syndrome, may have a common etiology. The Central Sensitization Inventory (CSI) may help physicians identify patients suffering from this group of disorders, known variously as central sensitization syndrome and dysfunctional pain. The CSI was found to have high reliability and validity (test-retest reliability = 0.82; Cronbach's alpha = 0.88). The data shown on this slide are drawn from a cohort of 121 patients who were referred to a multidisciplinary pain center, which specializes in the assessment and treatment of complex pain and psychophysiological disorders. A large percentage of patients (n = 89, 74%) met clinical criteria for one or more central sensitization/dysfunctional pain syndromes, and CSI scores were positively correlated with the number of diagnosed syndromes. In this population of pain sufferers, the most common diagnoses were tension headache/migraine (39%), myofascial pain syndrome (39%) and fibromyalgia (31%). Other diagnosed conditions included irritable bowel syndrome (15%), temporomandibular joint disorder (12%) and post-traumatic stress disorder (12%). Reference Neblett R et al. The Central Sensitization Inventory (CSI): establishing clinically significant values for identifying central sensitivity syndromes in an outpatient chronic pain sample. J Pain 2013; 14(5): Note: some patients had more than one diagnosis; less common diagnoses included restless leg syndrome (8%); chronic fatigue syndrome (4%) interstitial cystitis (4%), complex regional pain syndrome (2%) and multiple chemical sensitivity (1%) FM = fibromyalgia; IBS = irritable bowel syndrome; MPS = myofascial pain syndrome; PTSD = post-traumatic stress disorder; TH/M = tension headache/migraine; TMJ = temporomandibular joint disorder Neblett R et al. J Pain 2013; 14(5):

12 What is fibromyalgia? fibromyalgia is a common chronic widespread pain disorder, characterized by an amplification of pain signals, analogous to the “volume control setting” being turned up too high. Speaker’s Notes Fibromyalgia is a syndrome, not a disease. It is a common, chronic, persistent and debilitating widespread pain disorder that has a significant negative impact on patients’ quality of life. Fibromyalgia may be neurogenic in origin. It involves neurochemical imbalances in the central nervous system that are associated with central amplification of pain perception characterized by allodynia (heightened sensitivity to stimuli not normally painful) and hyperalgesia (increased response to painful stimuli). Reference Clauw DJ et al. The science of fibromyalgia. Mayo Clin Proc 2011; 86(9): Clauw DJ et al. Mayo Clin Proc 2011; 86(9):

13 Epidemiology of Fibromyalgia
Fibromyalgia is one of the most common central sensitization/dysfunctional conditions.1 Prevalence in USA is estimated to be 2–5% of the adult population.1 Fibromyalgia is highly underdiagnosed:2 Only 1 in 5 is diagnosed Diagnosis takes an average of 5 years3 Fibromyalgia occurs in all ages, both sexes and all cultures but occurs more frequently in:4 Women Those between the ages of 35 and 60 years Speaker's Notes It has been estimated that fibromyalgia affects 2–5% of the American adult population.1 However, this is undoubtedly a very conservative estimate, because fibromyalgia is highly underdiagnosed, with only one in five patients receiving a fibromyalgia diagnosis.2 Moreover, patients with fibromyalgia commonly experience symptoms for a number of years prior to diagnosis, and only after repeated investigations, referral to various specialists, and frequent healthcare visits.3 Although fibromyalgia occurs in patients of all ages, both genders, and in all cultures, it occurs more frequently in women. Most people are diagnosed during middle age and prevalence increases with age.4 References Wolfe F et al. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995; 38(1):19-28. Weir PT et al. The incidence of fibromyalgia and its associated comorbidities: a population-based retrospective cohort study based on International Classification of Diseases, 9th Revision codes. J Clin Rheumatol 2006; 12(3): National Pain Foundation. Fibromyalgia: Facts and Statistics. Available at: Accessed: July 21, 2009. White KP et al. The London Fibromyalgia Epidemiology Study: the prevalence of fibromyalgia syndrome in London, Ontario. J Rheumatol 1999; 26(7): USA = United States of America 1. Wolfe F et al. Arthritis Rheum 1995; 38(1):19-28; 2. Weir PT et al. J Clin Rheumatol 2006; 12(3):124-8; 3. National Pain Foundation. Fibromyalgia: Facts and Statistics. Available at: Accessed: July 21, 2009; 4. White KP et al. J Rheumatol 1999; 26(7):

14 Patient-Reported Impact of Fibromyalgia
Speaker's Notes Patients and physicians from three Latin American and six European countries were surveyed to describe differences in journey to diagnosis, impact, and management of fibromyalgia. A total of patients (300 from Latin America; 600 from Europe) and 1824 physicians (general practitioners or specialists; 604 from Latin America and 1220 from Europe) were surveyed. Patients and physicians completed separate questionnaires on symptoms, impact and fibromyalgia management. In Latin America vs. Europe, patients reported having fibromyalgia symptoms for longer (100.8 vs months, p <0.05), and taking longer to be diagnosed (42.3 vs months, p <0.05). Fibromyalgia was characterized by multiple symptoms (11.2 vs. 6.9), but more Latin American patients reported 14 common symptoms and rated pain higher on 11-point scale (8.0 vs. 7.2, p <0.05). Latin America patients were taking fewer medications (3.3 vs. 4.0). Patients from both regions found common symptoms very/extremely disruptive to their quality of life, but symptoms impacted daily living and ability to work more significantly in Latin America. Physicians from Latin American more often considered problems sleeping, difficulty concentrating, anxiety, depression, numbness/tingling, and leg cramps very/extremely disruptive vs. European physicians. Patients also considered 12/14 symptoms more disruptive than physicians in the same region. However, a higher proportion of physicians considered fibromyalgia to have a strong/very strong impact on aspects of daily living vs. patients within the same region. This slide shows the impact of fibromyalgia on overall quality of life as well as specific aspects of quality of life among the patients surveyed. Although there were some differences between the two geographical areas, this chart clearly shows that fibromyalgia has a strong negative impact on a variety of quality of life indicators. Reference Clark P et al. A patient and physician survey of fibromyalgia across Latin America and Europe. BMC Musculoskeletal Disorders 2013; 14:188. Clark P et al. BMC Musculoskelet Disord 2013; 14:188.

15 how do you identify patients with fibromyalgia in clinical practice?
Discussion Question how do you identify patients with fibromyalgia in clinical practice? Speaker’s Notes Ask the question shown on the slide to participants to stimulate discussion.

16 How to Recognize Fibromyalgia: Pain Is the Common Piece of the Puzzle
Leg cramps Restless legs Numbness/tingling Fatigue Pain Insomnia Speaker’s Notes While there are a variety of symptoms associated with fibromyalgia, as shown n this slide, pain is the central component. In 293 patients with fibromyalgia, Wolfe et al found that widespread pain (axial plus upper and lower segment plus left- and right-sided pain) was present in almost all (97.6%) patients with fibromyalgia compared with 69.1% of all control patients (n = 265). Reference Wolfe F 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): Nervousness Impaired memory/concentration Depression Wolfe F et al Arthritis Rheum 1990; 33(2):

17 Symptoms of Fibromyalgia
Pain, fatigue and sleep disturbance are present in at least 86% of patients* 100% 96% 100 86% 80 72% 60% 56% 60 52% 46% 42% 41% 40 Speaker’s Notes Chronic, widespread pain is the defining feature of fibromyalgia. In 293 patients with fibromyalgia, Wolfe et al found that widespread pain (axial plus upper and lower segment plus left- and right-sided pain) was present in almost all (97.6%) patients with fibromyalgia compared with 69.1% of all control patients (n = 265). In addition to pain, fatigue and sleep disturbances are the most common symptoms, occurring in ≥86% of patients with fibromyalgia. Other common physical symptoms associated with fibromyalgia include joint pain, headache, restless legs, numbness and tingling, and leg cramps. Psychological symptoms are not uncommon in patients with fibromyalgia. As is seen in other chronic pain conditions, such as low back pain, osteoarthritis or rheumatoid arthritis, mood disorders such as depression or anxiety are sometimes present in fibromyalgia. As depicted on this slide, as many as 20% of patients with fibromyalgia may present with major depression. Other psychological symptoms can include impaired concentration and nervousness. Reference Wolfe F 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): 32% 20% 20 Fatigue Insomnia Muscular pain Joint pains Headaches Restless legs Nervousness Impaired memory Leg cramps Major depression Impaired concentration Numbness and tingling *United States data Wolfe F et al Arthritis Rheum 1990; 33(2):

18 Core Clinical Features of Fibromyalgia
Widespread pain Neurocognitive impairment (“fibro fog”) Chronic, widespread pain is the defining feature of fibromyalgia Patient descriptors of pain include: Aching Exhausting Nagging Hurting Widespread Pain Chronic, widespread pain is the defining feature of fibromyalgia Patient descriptors of pain include: aching, exhausting, nagging, and hurting Presence of tender points Sleep disturbance/fatigue Mood disorders Speaker’s Notes Although the defining feature of fibromyalgia is chronic, widespread pain, neurocognitive impairment (“fibro fog”), sleep disturbances, fatigue, mood disorders, tenderness and morning stiffness may also be present. Patients often describe their pain as aching, exhausting, nagging or hurting. Cognitive dysfunction, which includes poor working memory, spatial memory alterations, free recall and verbal fluency, associates with pain in fibromyalgia as well as other pain patients and is different from healthy controls. “Fibro fog” is characterized by confusion, slowed processing of information and reaction time, difficulty in word retrieval or speaking, concentration, attention, short-term memory consolidation, and disorientation. Fibromyalgia-associated sleep disturbances are typically characterized by non-restorative sleep and increased awakenings. Abnormal components of sleep include sleep latency, sleep disturbance, and fragmented sleep leading to impaired daytime function. Poor sleep negatively impacts fatigue, affect and pain, with improvement in these parameters when sleep specifically is addressed. Other sleep disorders such as restless leg syndrome or sleep apnea may also occur in patients with fibromyalgia. Fatigue, reported to be present in over 90% of fibromyalgia patients, is the most common associated complaint. Fatigue may be more disabling than pain for some, and contributes to subjective report of functional impairment. Patients with fibromyalgia often describe their fatigue as physically or emotionally draining. Mood disorder, including depression and/or anxiety, is present in up to 75% of persons with fibromyalgia , but mood disorders and fibromyalgia are likely distinct. Anxiety commonly coexists with depression, but is also independently increased in fibromyalgia patients. Morning stiffness is also a common characteristic of fibromyalgia. References Carruthers BM et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment guidelines, a consensus document. J Chron Fat Synd 2003; 11(1):7-115. Harding SM. Sleep in fibromyalgia patients: subjective and objective findings. Am J Med Sci 1998; 315(6): Henriksson KG. Fibromyalgia – from syndrome to disease: overview of pathogenetic mechanisms. J Rehabil Med 2003; 41(41 Suppl):89-94. Leavitt F et al. Comparison of pain properties in fibromyalgia patients and rheumatoid arthritis patients. Arthritis Rheum 1986; 29(6): Roizenblatt S et al. Alpha sleep characteristics in fibromyalgia. Arthritis Rheum 2001; 44(1): Wolfe F 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): Wolfe F et al. Arthritis Rheum The prevalence and characteristics of fibromyalgia in the general population. 1995; 38(1):19-28. Morning stiffness Carruthers BM et al. J Chron Fat Synd 2003; 11(1):7-115; Harding SM. Am J Med Sci 1998; 315(6):367-37; Henriksson. J Rehabil Med 2003; 41(41 Suppl):89-94; Leavitt et al. Arthritis Rheum 1986; 29(6):775-81; Roizenblatt S et al. Arthritis Rheum 2001; 44(1):222-30; Wolfe F et al Arthritis Rheum 1990; 33(2):160-72; Wolfe F et al. Arthritis Rheum 1995; 38(1):19-28.

19 Many Fibromyalgia Patients Have Cognitive Complaints: “Fibro Fog”
Compared to those without the condition, patients with fibromyalgia complain more often of:1 Mental confusion Memory decline Speech difficulty Performance on cognitive tests shows they have poorer performance than age-matched controls on tasks involving:2 Working memory Recognition memory Free recall Verbal fluency Verbal knowledge Speaker’s Notes Compared with individuals without fibromyalgia, patients with fibromyalgia have more memory decline, mental confusion and speech difficulty. Memory decline and mental confusion are coupled more often in patients with fibromyalgia than in patients without fibromyalgia. Patients with fibromyalgia with this combination of cognitive problems report more pain, stiffness, fatigue and disturbed sleep compared with patients with fibromyalgia with memory problems alone. Patients with rheumatic disease substantially differ in cognitive vulnerability, with patients with fibromyalgia at considerably higher risk for cognitive difficulty. The prevalence of a combined disturbance in memory and mental clarity is high and closely associated with the perception of increased illness severity and diminished mental health in fibromyalgia. Fibromyalgia patients perform more poorly on measures of working memory function, free recall, verbal fluency and verbal knowledge, but retain speed of processing relative to age-matched controls. The loss of mental clarity and problems with memory associated with fibromyalgia has been dubbed "fibro fog.“ References Katz RS et al. The prevalence and clinical impact of reported cognitive difficulties (fibrofog) in patients with rheumatic disease with and without fibromyalgia. J Clin Rheumatol 2004; 10(2):53-8. Park DC et al. Cognitive function in fibromyalgia patients. Arthritis Rheum 2001; 44(9): 1. Katz RS et al. J Clin Rheumatol 2004; 10(2):53-8; 2.Park DC et al. Arthritis Rheum 2001; 44(9):

20 Sleep Disturbances and Fibromyalgia
deprivation Pain Disturbed sleep may contribute to enhanced pain Enhanced pain may contribute to increases in sleep disturbances Speaker’s Notes Patients with fibromyalgia often have problems with sleep, including non-restorative sleep, insomnia, early morning awakening and poor quality of sleep. Studies have shown sleep quality to be significantly lower in patients with fibromyalgia than in controls, and patients report worsening of pain after poor sleep. Sleep studies have shown that alpha-delta sleep patterns associated with interrupted and non- restorative sleep are frequently observed in patients with fibromyalgia. Sleep disturbances may be related to the reduced energy and fatigue often found among patients with fibromyalgia. Disturbed sleep may also contribute to enhanced pain. Frequent alpha-wave intrusions during delta-wave sleep have been associated with the reduced production of growth hormone (GH) and insulin-like growth factor (IGF-1). Because GH and IGF-1 are necessary for the repair of muscle microtrauma, sleep disturbances may impair the healing of muscle tissue damage, thereby prolonging the transmission of sensory stimuli from damaged muscle tissue to the central nervous system and enhance the perception of muscle pain, which may contribute to increases in sleep disturbance, thereby maintaining the patient’s fatigue and continuing the inadequate muscle tissue repair. Reference Bradley LA. Pathophysiology of fibromyalgia. Am J Med 2009; 122(12 Suppl):S22-30. Fibromyalgia patients may complain of: Non-restorative sleep Insomnia Early morning awakening Poor sleep quality Bradley LA. Am J Med 2009; 122(12 Suppl):S22-30.

21 Mood Disorders and Fibromyalgia
At time of diagnosis 20–40% have an identifiable mood disorder Lifetime prevalence Depression: 75% Anxiety: 60% Speaker’s Notes At the time of fibromyalgia diagnosis, 20–40% of fibromyalgia patients have an identifiable mood disorder. Mood disorder, including depression and/or anxiety, is present in up to 75% of persons with fibromyalgia , but mood disorders and fibromyalgia are likely distinct. Anxiety commonly coexists with depression, but is also independently increased in fibromyalgia patients. Depression is influenced by low family cohesion, high pain and helplessness, and passive coping skills. In many cases, depression or anxiety may be the result of chronic pain. First-degree relatives of individuals with either fibromyalgia or major depressive disorder demonstrated similar rates of major depressive disorder suggesting that these two conditions share similar risk factors, which may be genetically driven. Seventy-five percent of individuals with fibromyalgia are likely to suffer from depression over their lifetime, while 60% will suffer from anxiety over their lives. References Arnold LM et al. Family study of fibromyalgia. Arthritis Rheum 2004; 50(3): Boissevain MD, McCain GA. Toward an integrated understanding of fibromyalgia syndrome. I. Medical and pathophysiological aspects. Pain 1991; 45(3): Boissevain MD, McCain GA. Toward an integrated understanding of fibromyalgia syndrome. II. Psychological and phenomenological aspects. Pain 1991; 45(3): Fishbain DA et al. Impact of chronic pain patients' job perception variables on actual return to work. Clin J Pain 1997; 13(2): Giesecke T et al. Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum 2003; 48(10): Katon W et al. Medical symptoms without identified pathology: relationship to psychiatric disorders, childhood and adult trauma, and personality traits. Ann Intern Med 2001; 134(9 Pt 2): In many cases, depression or anxiety may be the result of chronic pain. Arnold LM et al. Arthritis Rheum 2004; 50(3):944-52; Boissevain MD, McCain GA. Pain 1991; 45(3):227-38; Boissevain MD, McCain GA. Pain 1991; 45(3):239-48; Fishbain DA et al. Clin J Pain 1997; 13(2):116-37; Giesecke T et al. Arthritis Rheum 2003; 48(10): ; Katon W et al. Ann Intern Med 2001; 134(9 Pt 2):

22 The Paradigm of Pain: Interrelationship Among Pain, Sleep Disturbance and Psychological Symptoms
Functional impairment and fatigue Pain Related Sleep disturbances can directly result from and/or contribute to fibromyalgia. Psychological symptoms are strongly associated with fibromyalgia. Speaker’s Notes The complex interrelationship between pain, sleep, and psychological symptoms is expressed as a paradigm in which the pain-related symptoms (comorbid conditions) exacerbate each other and create a vicious circle of suffering. There is a need to assess the patient as a whole when evaluating fibromyalgia. Additionally, fibromyalgia and pain-related symptoms can have a profound effect on a patient’s quality of life and functionality. These conditions often exacerbate each other and make pain feel worse or even have a negative impact on treatment. Sleep interference: pain results in low sleep efficiency, frequent nighttime awakenings, and poor sleep quality and restfulness. Therefore, sleep interference can directly result from and exacerbate fibromyalgia and psychological symptoms. The majority of fibromyalgia patients cite pain as the sole reason for their sleep disturbances. Psychological symptoms: psychological symptoms such as anxiety and depression are strongly associated with fibromyalgia. Treatment: management strategies should address the treatment of patients as a whole and not just the pain component, to improve overall patient functionality. Treatment of fibromyalgia can be optimized by using agents that effectively address the pain as well as pain- related symptoms and by consequently reducing polypharmacy. Reference Argoff CD. The coexistence of neuropathic pain, sleep, and psychiatric disorders: a novel treatment approach. Clin J Pain 2007; 23(1):15-22. Management strategy for fibromyalgia patients is to improve overall patient functionality. Adapted from: Argoff CE. Clin J Pain 2007; 23(1):15-22.

23 Diagnosing Fibromyalgia
On average it takes patients >2 years to be diagnosed with fibromyalgia A estimated 75% of people with fibromyalgia remain undiagnosed Overview of Diagnosis History of fibromyalgia or related conditions Personal and family history Physical examination Most important to identify any other possible conditions Differential diagnosis Clinical/laboratory evaluation to identify other possible conditions Consequences of Non-diagnosis Failure to diagnose fibromyalgia is associated with increased costs and increased use of medical resources Speaker’s Notes The diagnosis of fibromyalgia is not straight forward. In fact, on average, patients are not diagnosed for more than two years after the onset of symptoms and an estimated 75% of patients with fibromyalgia go undiagnosed. A diagnosis of fibromyalgia is made following a clinical evaluation, which includes a history of current complaints, attention to past health status and a physical examination, without any confirmatory diagnostic test. Physical examination is very important to identify any other possible conditions. The physician should consider the established diagnostic criteria for fibromyalgia, rule out other reasons for diffuse body pain, and perform a tender point exam. A differential diagnosis can be made by excluding other conditions such as osteoarthritis, rheumatoid arthritis, polymyalgia rheumatica, hypothyroidism, lupus and Sjögren’s syndrome. This can be achieved through clinical and laboratory evaluations. Note: extensive lab evaluation is usually not necessary to rule out fibromyalgia. In some cases, a thyroid-stimulating hormone test may be called for. Polymyalgia rheumatica seldom occurs under the age of 60, whereas the onset of fibromyalgia after 65 years is rare. References Annemans L et al. Health economic consequences related to the diagnosis of fibromyalgia syndrome. Arthritis Rheum 58(3): Choy E et al. A patient survey of the impact of fibromyalgia and the journey to diagnosis. BMC Health Serv Res 2010; 10:102. Clauw DJ et al. The science of fibromyalgia. Mayo Clin Proc 2011; 86(9): Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment. J Rheumatol 2005; 32(Suppl 75):6-21. Wolfe F 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): Annemans L et al. Arthritis Rheum 58(3): ; Choy E et al. BMC Health Serv Res 2010; 10:102; Clauw DJ et al. Mayo Clin Proc. 2011; 86(9):907-11; Mease P. J Rheumatol 2005; 32(Suppl 75):6-21; Wolfe F et al. Arthritis Rheum 1990; 33(2):

24 Differential Diagnosis of Fibromyalgia
Hypothyroidism Vitamin D deficiency Inflammatory rheumatic disease Cancer Inflammatory muscle diseases Speaker’s Notes Many cases of fibromyalgia do not precisely align with a standardized set of diagnostic criteria. However, it is not believed to be a diagnosis of exclusion, although some health care providers have labeled it as such. Because there is an absence of absolute, definitive diagnostic criteria with universal applicability, providers often settle upon this diagnosis following negative testing for other differentials. Rather than assuming a diagnosis of fibromyalgia, carefully considering a multitude of potential diagnoses, as shown in this slide, will decrease the likelihood of a misdiagnosis. Some of the common differentials to consider in patients exhibiting symptoms of fibromyalgia are hypothyroidism, vitamin D deficiency, cancer, inflammatory muscle disease and inflammatory rheumatic diseases. Rahman A et al. Fibromyalgia. BMJ 2014; 348:g1224. Rahman A et al. BMJ 2014; 348:g1224.

25 Patients with Fibromyalgia Present with a Global Pain Disorder
4/16/2017 Patients with Fibromyalgia Present with a Global Pain Disorder This is a pain drawing Patient colors all areas of the body in which he or she feels pain1 The diagram shows that the pain of fibromyalgia is widespread2 Speaker’s Notes The pain of fibromyalgia is widespread.1 Typically, fibromyalgia patients present with complaints of diffuse body pain. Pain drawings can be used to characterize the location and size of painful areas. When fibromyalgia patients are asked to color in areas that are painful, they typically shade in areas all over the body to indicate their widespread pain.2 References Silverman SL, Martin SA. In: Wallace DJ, Clauw DJ (eds). Fibromyalgia & Other Central Pain Syndromes. Lippincott, Williams & Wilkins; Philadelphia, PA: 2005. Wolfe F 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): Back Front Adapted from pain drawing provided courtesy of L Bateman. 1. Silverman SL, Martin SA. In: Wallace DJ, Clauws DJ (eds.). Fibromyalgia & Other Central Pain Syndromes. Lippincott, Williams & Wilkins; Philadelphia, PA: 2005; 2. Wolfe F et al. Arthritis Rheum 1990; 33(2):

26 ACR Classification Criteria for Fibromyalgia (1990)
ACR criteria: History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points ACR criteria are both sensitive (88.4%) and specific (81.1%) Speaker’s Notes The 1990 ACR criteria for the classification for fibromyalgia require that patients have a history of chronic pain for ≥3 months and pain in ≥11 of 18 tender point sites on digital palpation. To determine the criteria for the classification of fibromyalgia, Wolfe et al studied 558 patients; widespread pain, defined as axial plus upper and lower segment plus left- and right-sided pain, was demonstrated in 97.6% of fibromyalgia patients (n = 293) and 69.1% of control patients (n = 265). Controls were age- and sex-matched patients with neck pain syndromes, low back pain syndromes, trauma-related pain syndromes, and possible systemic lupus erythematosus or rheumatoid arthritis. Sleep disturbances, fatigue and morning stiffness were present in >75% of fibromyalgia patients. Although the ACR criteria can be used to differentiate fibromyalgia from other rheumatologic conditions, the criteria were originally intended as a research tool. Therefore, it is important to note that the ACR criteria are useful for classification of fibromyalgia but not for diagnosis. “Expert opinion” remains the gold standard in making a diagnosis of fibromyalgia. There are no objective findings for fibromyalgia on physical exam or from laboratory tests. Although Wolfe et al found tender points were the most powerful discriminator between fibromyalgia patients and controls, tenderness is subjective and depends upon the examiner’s strength of palpation. It should be noted that Wolfe et al reported the ACR criteria are sensitive (88.4%) and specific (81.1%) for fibromyalgia; this was not demonstrated outside a rheumatology clinic. Reference Wolfe F 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): ACR = American College of Rheumatology Wolfe F et al. Arthritis Rheum 1990; 33(2):

27 Performing a Manual Tender Point Survey
Digital palpation with an approximate force of 4 kg Estimated pressure needed to turn the examiner’s thumbnail white upon depressing For a “positive” tender point, subject must state palpation was painful Accuracy for fibromyalgia: Sensitivity: 88.4% Specificity: 81.1% Controversies regarding tender point evaluation: Subjective May not be necessary for diagnostic studies What about fewer than 11 of 18 tender points? Speaker’s Notes The Manual Tender Point Survey, based on the 1990 American College of Rheumatology tender point protocol for fibromyalgia, takes about 5–10 minutes to perform. The standard procedure for applying pressure uses the thumb pad of the examiner's dominant hand. This method has been shown to be as reliable as the use of a dolorimeter (strain gauge) and allows the examiner to make use of important tactile cues. Survey sites are first located visually, and then with light palpation. Thumb pressure is then applied perpendicular to each survey site. Each site is pressed for 4 seconds only once to avoid sensitization that may occur with repeated palpation. The force is increased by 1 kg/second until 4 kg of pressure is achieved. Whitening of the examiner's nail bed usually occurs when applying the 4 kg of pressure. A number of factors may influence the sensitivity of tender points during an examination: (1) amount of force applied at the survey site, (2) number of times (single vs. repeated) and method (finger pad, dolorimeter) by which the force is applied, and (3) patient's position, which affects muscle tone and survey site localization. The sequence of site examination may influence the patient's response based on the anchoring effect of sensations experienced at prior survey sites. A standardized procedure enhances the reliability of the test. According to Wolfe et al, these criteria are sensitive (88.4%) and specific (81.1%) for fibromyalgia. However, the method remains controversial due to its subjective nature and the fact that it does not account for patients who have fewer than 11 tender points but who may still have fibromyalgia. References National Fibromyalgia Association. The Manual Tender Point Survey. Available at: Accessed: August 13, 2013. Wilke WS. New developments in the diagnosis of fibromyalgia syndrome: say goodbye to tender points? Cleve Clin J Med 2009; 76(6): Wolfe F 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): National Fibromyalgia Association. The Manual Tender Point Survey. Available at Accessed August 13, 2013; Wilke WS. Cleve Clin J Med 2009; 76(6):345-52; Wolfe F et al. Arthritis Rheum 1990; 33(2):

28 ACR Proposed Diagnostic Criteria for Fibromyalgia (2010)
Fibromyalgia can be diagnosed if: Patient experiences widespread pain and associated symptoms Symptoms have been present at same level for ≥3 months No other condition otherwise explains the pain Associated symptoms include: Unrefreshed sleep Cognitive symptoms Fatigue Other somatic symptoms Speaker’s Notes Over time, a series of objections to the 1990 ACR classification criteria for fibromyalgia developed. First, it became increasingly clear that the tender point count was rarely performed in primary care where most fibromyalgia diagnoses occurred, and when performed, was performed incorrectly. Many physicians did not know how to examine for tender points and some simply refused to do so. Consequently, fibromyalgia diagnosis in practice has often been a symptom-based diagnosis. Second, the importance of certain symptoms, such as fatigue, cognitive symptoms and the extent of somatic symptoms, were not considered when the 1990 guidelines were developed. Additionally, many fibromyalgia experts believed tender points obscured important considerations and erroneously linked the disorder to peripheral muscle abnormality. Finally, some physicians considered that fibromyalgia was a spectrum disorder and was not well served by dichotomous criteria. Another important problem was that patients who improved or whose symptoms and tender points decreased could fail to satisfy the ACR 1990 classification definition. It was not clear how to categorize or assess these patients. In addition, the ACR classification criteria set such a high bar for diagnosis that there was little variation in symptoms among fibromyalgia patients. These two considerations suggested the need for a broad-based severity scale that could differentiate among patients according to the level of fibromyalgia symptoms. As a result, in 2010, the ACR proposed that a patient satisfies diagnostic criteria for fibromyalgia if the following three conditions are met: Widespread Pain Index (WPI) score of 7 and symptom severity (SS) scale score of 5 or WPI of 3–6 and SS scale score of 9 Symptoms have been present at a similar level for ≥3 months The patient does not have a disorder that would otherwise explain the pain Reference Wolfe F et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken) 2010; 62(5): ACR = American College of Rheumatology Wolfe F et al. Arthritis Care Res (Hoboken) 2010; 62(5):

29 FiRST: Fibromyalgia Rapid Screening Tool
Self-administered 6-item questionnaire Score of ≥5 is indicative of fibromyalgia Sensitivity: 90.5% Specificity: 85.7% Items I have pain all over my body. My pain is accompanied by continuous and very unpleasant general fatigue. My pain feels like burns, electric shocks or cramps. My pain is accompanied by other unusual sensations throughout my body, such as pins and needles, tingling or numbness. My pain is accompanied by other health problems such as digestive problems, urinary problems, headaches or restless legs. My pain has a significant impact on my life, particularly on my sleep and my ability to concentrate, making me feel slower generally. Speaker’s Notes The Fibromyalgia Rapid Screening Tool (FiRST) was developed to detect fibromyalgia in patients with diffuse chronic pain. It is important to note that this tool is useful for screening for fibromyalgia but not for diagnosis. Items requiring "yes/no" responses and relating to the most relevant clinical characteristics of fibromyalgia were compiled by a group of rheumatologists and pain experts. The provisional questionnaire was tested in a prospective multicenter study of 162 patients with chronic pain due to fibromyalgia (according to American College of Rheumatology [ACR] criteria) (n = 92) compared with a group of patients with chronic diffuse pain due to other rheumatic conditions, including rheumatoid arthritis (n = 32), ankylosing spondylitis (n = 25) and osteoarthritis (n = 13). Identification of the most discriminant combinations of items for fibromyalgia and the calculation of their sensitivity and specificity were based on both univariate and multivariate (stepwise logistic regression) analyses. The assessment of the psychometric properties of the questionnaire also dealt with face validity, content validity, test-retest reliability and convergent/divergent validity. Based on univariate and multivariate analyses, six items were retained in the final version of FiRST. These items were used to calculate the sensitivity, specificity and predictive accuracy of the questionnaire. A score of 5 or more is indicative of fibromyalgia with a sensitivity of 90.5% and a specificity of 85.7%. Reference Perrot S et al. Development and validation of the Fibromyalgia Rapid Screening Tool (FiRST). Pain 2010; 150(2):250-6. Perrot S et al. Pain 2010; 150(2):250-6.

30 Discussion Question What do you tell your patients you think are suffering from fibromyalgia? Speaker’s Notes Ask the question shown on the slide to participants to stimulate discussion.

31 Tips on Providing the Diagnosis of Fibromyalgia
Be specific about the diagnosis Be positive about the diagnosis Promote and encourage patient self-efficacy around the disease but... Set realistic expectations Emphasize there is no cure but improved control of symptoms is usually possible Speaker’s Notes This slide lists several tips for providing a patient with a diagnosis of fibromyalgia. It is important to be both specific and positive about the diagnosis. It is important to promote and encourage patient self-efficacy around fibromyalgia, but it is equally important to ensure patients have realistic expectations for therapies and to emphasize that while improved control of symptoms is usually possible, there is no cure for fibromyalgia. Reference Arnold LM et al. A framework for fibromyalgia management for primary care providers. Mayo Clin Proc 2012; 87(5): Arnold LM et al. Mayo Clin Proc 2012; 87(5):

32 Diagnosis of Fibromyalgia Can Improve Patient Satisfaction
IMPROVEMENT Speaker’s Notes For a variety of reasons, the labeling of certain chronic pain patients as having fibromyalgia sparked much debate. One of the arguments was that the label of fibromyalgia , in itself, might precipitate or exacerbate behavior that has been variably termed “illness behavior,” “learned pain” and “learned helplessness”. This might result in heightened symptoms, worsened function, increased disability claims and increased health care-seeking behavior. To determine if assigning the label of fibromyalgia to individuals with chronic widespread pain has a significant effect on long-term health status, function, and health service utilization, White et al conducted the London Fibromyalgia Epidemiology Study in which 100 individuals with fibromyalgia were identified by screening non-institutionalized adults. Only 28 of the 100 had been previously diagnosed with fibromyalgia; for 72, the diagnostic label was new. All 28 with pre-diagnosed fibromyalgia were female compared with 58 of the 72 newly diagnosed cases. The researchers compared previously non-labeled fibromyalgia cases at study entry (pre-labeling) and at 18 and 36 months follow-up (post-labeling) with respect to general health status, fibromyalgia -related symptoms, and all items from the Fibromyalgia Impact Questionnaire (FIQ) (including total FIQ score, and several measures of health service utilization) to determine if health status, function and health services utilization had changed. Fifty-six (78%) of the original 72 newly diagnosed fibromyalgia cases were available for reassessment at 18 months, and 43 (60%) at 36 months. Although physical functioning decreased slightly over time, by 36 months, the newly diagnosed fibromyalgia cases reported a clinically and statistically significant decrease in dissatisfaction with health (2.2 vs. 3.0 on a five-point Likert scale; 95% confidence interval 1.2–0.4). No other differences in clinical status or health service use occurred over time. Therefore, it appears that the fibromyalgia label does not have a meaningful adverse effect on clinical outcome over the long term. Note that investigators did not control for treatment patients may have received post-diagnosis; therefore, this improvement may have been the result of having received treatment earlier. Reference White KP 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 chronic widespread pain. Arthritis Rheum 2002; 47(3):260-5. *Statistically significant vs. baseline (confidence interval -1.2 to -0.4) White KP et al. Arthritis Rheum 2002; 47(3):260-5.

33 Discussion Question what non-pharmacological approaches could you use to help address fibromyalgia from a biopsychosocial perspective? Speaker’s Notes Ask the question shown on the slide to participants to stimulate discussion.

34 Multimodal Treatment of Fibromyalgia Based on Biopsychosocial Approach
Cognitive behavioral therapy Education Sleep hygiene Multimodal treatment of pain Self-management support Pharmacotherapy Speaker’s Notes Many complex chronic diseases are effectively managed in primary care, supported by collaboration with health care specialists in a patient-centered approach. Management of patients with fibromyalgia in the primary care setting should be approached in a similar manner, by implementation of a chronic care framework based on core principles of education, goal setting, multidisciplinary management, routine monitoring, and outcomes assessment (focusing on improvement in symptoms, physical and emotional functioning, and overall health-related quality of life). Follow-up should involve specific resources that help health care professionals educate patients and their families to engage in self-management and carry out ongoing assessment to track disease status over time. Because no single treatment approach for fibromyalgia targets all symptoms or will manage every patient, there is a clear need for a dynamic, multifaceted approach to management. Reference Arnold LM et al. A framework for fibromyalgia management for primary care providers. Mayo Clin Proc 2012; 87(5): Treat comorbid conditions Manage expectations Physical therapy Arnold LM et al. Mayo Clin Proc 2012; 87(5):

35 Non-pharmacological Treatment of Fibromyalgia
Sleep hygiene Physical activity Cognitive behavioral therapy Self-management support Speaker’s Notes Several non-pharmacological approaches are beneficial to patients with fibromyalgia, reducing pain and improving function. It may be helpful to incorporate appropriate non-pharmacological approaches into the overall treatment plan as written “prescriptions” to highlight their equal importance to medications. Among the non- pharmacological approaches that have demonstrated efficacy in clinical trials are exercise; sleep hygiene; some forms of cognitive behavioral therapy, and ongoing patient education. Other non-pharmacological approaches, such as yoga, massage and other types of physical therapy, may also be considered. An integrated approach is key, and the importance of self-management should be highlighted. Providing materials that promote basic self-management techniques to accomplish daily activities and manage symptoms, in addition to suggesting ways to incorporate wellness activities into daily life, should form the foundation of guided self-management. Reference Arnold LM et al. A framework for fibromyalgia management for primary care providers. Mayo Clin Proc 2012; 87(5): Seek support from other health care professionals – nurses, social workers, occupational therapists, physiotherapists, psychologists, psychiatrists, etc. Arnold LM et al. Mayo Clin Proc 2012; 87(5):

36 Non-pharmacologic Interventions to Improve Sleep in Fibromyalgia
Avoid stimulants Go to bed and rise at regular times Avoid napping through day Exercise regularly, particularly in the afternoon Use the bed only for sleep and sex Relax before bed Printed information on sleep for patients Speaker’s Notes This slide lists some essentials of good sleep habits. It may be helpful to provide printed information on sleep to patients. Reference University of Maryland Medical Center. Sleep Hygiene. Available at: Accessed: August 21, 2013. University of Maryland Medical Center. Sleep Hygiene. Available at: Accessed: August 21, 2013.

37 Physical Activity and Fibromyalgia
Benefits Recommendations for Fibromyalgia Stimulates release of endorphins and enkephalins within 30 minutes These bind to opioid receptors, reducing pain by an action on both ascending and descending neural pathways Type of Exercise Try to include different types in one session (e.g., aerobic, strengthening, stretching) Patient preference and availability should guide selection Intensity Start low, go slow Gradually increase to reach moderate intensity level Speaker’s Notes Exercise can be beneficial because it stimulates release of endorphins and enkephalins within 30 minutes. These molecules bind to opioid receptors and reduce pain by an action on both ascending and descending neural pathways. Exercise is commonly recommended in the management of people with fibromyalgia, and interest in examining exercise benefits for those with the syndrome has grown substantially over the past 25 years. Research supports aerobic and strength training to improve physical fitness and function, reduce fibromyalgia symptoms and improve quality of life. However, other forms of exercise (e.g., tai chi, yoga, Nordic walking, vibration techniques) and lifestyle physical activity also have been investigated to determine their effects. In the management of fibromyalgia, it may be beneficial for patients to include different types of exercise, such as aerobic and strength training combined with stretching, in one session. In recommending exercise therapy, practitioners should take patient preference and the availability of activities into account. Patients with fibromyalgia starting on an exercise program should start at a low intensity and slowly and gradually increase the intensity to a moderate level. References Busch AJ et al. Exercise therapy for fibromyalgia. Curr Pain Headache Rep 2011; 15(5): McGovern MK. The Effects of Exercise on the Brain. Available at: Accessed: July 25, 2013. Busch AJ et al. Curr Pain Headache Rep 2011; 15(5):358-67; McGovern MK. The Effects of Exercise on the Brain. Available at: Accessed: July 25, 2013.

38 Cognitive Behavioral Therapy in Fibromyalgia
Technique Learn to identify emotions that influence cognitive and affective components of pain (anxiety, helplessness, depression) Employ active cognitive, problem-solving and distraction/relaxation techniques to modify emotions Develop active strategies targeting well-being and control Speaker’s Notes In cognitive behavioral therapy, patients learn to identify emotions such as anxiety, helplessness, and depression that influence cognitive and affective components of pain. The technique employs active cognitive problem solving and distraction/relaxation techniques to modify emotions. This can help patients develop active strategies that target overall well-being and control. Reference Thieme K, Turk DC. Cognitive-behavioral and operant-behavioral therapy for people with fibromyalgia. Reumatismo 2012; 64(4): Thieme K, Turk DC. Reumatismo 2012; 64(4):

39 is fibromyalgia “all in their head”?
Discussion Question is fibromyalgia “all in their head”? What are the pathophysiological mechanisms behind the pain these patients experience? Speaker’s Notes Ask the question shown on the slide to participants to stimulate discussion.

40 Fibromyalgia: An Amplified Pain Response
4/16/2017 Fibromyalgia: An Amplified Pain Response 10 Pain in fibromyalgia Normal pain response 8 Pain amplification response Hyperalgesia (when a pinprick causes an intense stabbing sensation) 6 Subjective pain intensity 4 Allodynia (hugs that feel painful) Speaker’s Notes In addition to immediate unpleasantness, painful experiences can imprint themselves indelibly on the nervous system, amplifying the response to subsequent noxious stimuli and causing typically painless sensations to be experienced as pain. A chronic condition sometimes develops that produces continuous pain. Noxious stimuli can sensitize the nervous system response to subsequent stimuli. The normal pain response as a function of stimulus intensity is depicted by the curve at the right, where even strong stimuli are not experienced as pain. However, a traumatic injury can shift the curve to the left. Then, noxious stimuli become more painful (hyperalgesia) and typically painless stimuli are experienced as pain (allodynia). In the normal pain response, pain intensity increases as the stimulus intensity increases. Due to central sensitization, fibromyalgia patients have an amplification of pain response, which presents an increased response at lower stimuli, causing the curve to shift to the left. In fibromyalgia patients, lower stimulus produces an elevated subjective pain intensity demonstrated by hyperalgesia, in which noxious stimuli cause greater and more prolonged pain and allodynia, in which pain results from normally painless stimuli Reference Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician 2001; 63(1): 2 Stimulus intensity Adapted from: Gottschalk A, Smith DS. Am Fam Physician 2001; 63(10):

41 Pathophysiological Changes in Fibromyalgia
Altered intrinsic connectivity Gray matter atrophy Brain fMRI studies show marked regional increase in cerebral blood flow following a painful stimulus in patients with fibromyalgia compared to controls Exaggerated pain perception Altered metabolite levels in pain-processing regions of brain Deficit in endogenous pain inhibitory systems noted Increased levels of pain neurotransmitter substance P (>3x) Pain amplification Speaker’s Notes Fibromyalgia is characterized by a heightened sensitivity to pain. Although the pathogenesis of fibromyalgia is not completely understood, alterations of the central nervous system (CNS) may contribute to the chronic pain of fibromyalgia. In patients with fibromyalgia , sensory input that would normally invoke an innocuous response may instead result in pain. CNS mechanisms, such as central sensitization, may explain the generalized pain hypersensitivity of individuals with fibromyalgia. Recent data suggest that increased levels of excitatory neurotransmitters (glutamate and substance P) may contribute to neuronal hyperactivity and central sensitization. Secondary pain is transmitted by unmyelinated C fibers and is related to chronic pain states. It is described as dull, aching or burning. Repetitive stimulation of C fibers can result in pain amplification in the dorsal horn neurons of the spinal cord. This is known as wind-up and is thought to result from central mechanisms. Patients with fibromyalgia demonstrate abnormal wind-up; this provides additional evidence that central mechanisms may be involved in fibromyalgia. Other changes include altered intrinsic connectivity , impaired small fiber function and gray matter atrophy. References Feraco P et al. Metabolic abnormalities in pain-processing regions of patients with fibromyalgia: a 3T MR spectroscopy study. AJNR Am J Neuroradiol 2011; 32(9): Gracely RH et al. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 2002; 46(5): Julien N et al. Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain 2005; 114(1-2): Napadow V et al. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum 2010; 62(8): Robinson ME et al. Gray matter volumes of pain-related brain areas are decreased in fibromyalgia syndrome. J Pain 2011; 12(4): Russell IJ et al. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum ; 37(11): Üçeyler N et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013; 136(Pt 6): Vaerøy H et al. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain 1988; 32(1):21-6. Minimal stimuli Nociceptive afferent fiber Impaired small fiber function Spinal cord fMRI = functional magnetic resonance imaging Feraco P et al. AJNR Am J Neuroradiol 2011; 32(9): ; Gracely RH et al. Arthritis Rheum 2002; 46(5): ; Julien N et al. Pain 2005; 114(1-2): ; Napadow V et al. Arthritis Rheum 2010; 62(8): ; Robinson ME et al. J Pain 2011; 12(4):436-43; Russell IJ et al. Arthritis Rheum 1994; 37(11): ; Üçeyler N et al. Brain 2013; 136(Pt 6):1857-6; Vaerøy H et al. Pain 1988; 32(1):21-6.

42 Central Sensitization Produces Abnormal Pain Signaling
Brain Pain treatment options α2δ ligands Antidepressants Perceived pain (hyperalgesia/ allodynia) Increased release of pain neurotransmitters glutamate and substance P Pain amplification Speaker’s Notes Central sensitization results from an increase in excitatory mechanisms or a decrease in inhibitory mechanisms. It is thought to be responsible for tactile allodynia (pain in response to light brushing of the skin) and for the spread of heightened pain sensitivity beyond an area of tissue damage so that adjacent non-damaged tissue is tender. Essentially, input from nociceptive afferent nerves causes a release of excitatory neurotransmitters (glutamate and substance P) in the dorsal horn of the spinal cord. These neurotransmitters may contribute to neuronal hyperactivity and central sensitization. After central sensitization has been established, only minimal nociceptive input is required for the maintenance of a chronic pain state. Pharmacological options for the management of pain due to central sensitization include α2δ ligands and antidepressants. References Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006; 52(1):77-92. Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician 2001; 63(10) Henriksson KG. Fibromyalgia–from syndrome to disease: overview of pathogenetic mechanisms. J Rehabil Med 2003; 41(Suppl):89-94. Larson AA et al. Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways. Pain 2000; 87(2): Marchand S. The physiology of pain mechanisms: from the periphery to the brain. Rheum Dis Clin North Am 2008; 34(2): Rao SG. The neuropharmacology of centrally-acting analgesic medications in fibromyalgia. Rheum Dis Clin North Am 2002; 28(2): Staud R. Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome. Arthritis Res Ther 2006; 8(3): Staud R, Rodriguez ME. Mechanisms of disease: pain in fibromyalgia syndrome. Nat Clin Pract Rheumatol 2006; 2(2):90-8. Vaerøy H et al. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain 1988; 32(1):21-6. Woolf CJ et al. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004; 140(6): Increased neuronal excitability Minimal stimuli Nociceptive afferent fiber Spinal cord Adapted from: Campbell JN, Meyer RA. Neuron 2006; 52(1):77-92; Gottschalk A, Smith DS. Am Fam Physician 2001; 63(10) ; Henriksson KG. J Rehabil Med 2003; 41(Suppl):89-94; Larson AA et al. Pain 2000; 87(2):201-11; Marchand S. Rheum Dis Clin North Am 2008; 34(2): ; Rao SG. Rheum Dis Clin North Am 2002; 28(2):235-59; Staud R. Arthritis Res Ther 2006; 8(3):208-14; Staud R, Rodriguez ME. Nat Clin Pract Rheumatol 2006; 2(2):90-8; Vaerøy H et al. Pain 1988; 32(1):21-6; Woolf CJ et al. Ann Intern Med 2004; 140(6):

43 Loss of Inhibitory Control: Disinhibition
Brain Pain treatment options α2δ ligands Antidepressants Perception Exaggerated pain perception X Noxious stimuli Descending modulation X Ascending input Speaker’s Notes This slide illustrates how nervous system injury can reduce inhibition in the dorsal horn through various mechanisms. Stimulation of inhibitory interneurons located in the dorsal horn of the spinal cord releases neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine, which have the effect of reducing synaptic transmission of sensory impulses. Inhibitory mechanisms that arise from descending pathways from the brain are mediated by endogenous opioids or neurotransmitters, such as serotonin and noradrenaline. This inhibitory system prevents overstimulation.  Experimental peripheral nerve injuries in animals have been associated with decreased GABA and glycine levels. In addition, GABA receptors and opioid receptors are down-regulated following nerve injury. It has been hypothesized that if inhibitory controls are lost or impaired, then excitatory mechanisms may dominate, allowing dorsal horn neurons to fire in an exaggerated way in response to noxious input which may eventually result in an increased pain perception. In chronic pain states there is increasing deficit of descending inhibition. References Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand Suppl 1999; 173:12-24. Doubell TP et al. In: Wall PD, Melzack R (eds). Textbook of Pain. 4th ed. Harcourt Publishers Limited; Edinburgh, UK: 1999. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353(9168): Transmission Transduction Nociceptive afferent fiber Spinal cord Attal N, Bouhassira D. Acta Neurol Scand 1999; 173:12-24; Doubell TP et al. In: Wall PD, Melzack R (eds). Textbook of Pain. 4th ed. Harcourt Publishers Limited; Edinburgh, UK: 1999; Woolf CJ, Mannion RJ. Lancet 1999; 353(9168):

44 How a2d Ligands Decrease Pain Sensitivity
Binding of α2δ ligands to α2δ inhibits calcium channel transport Calcium channels transported to nerve terminals in dorsal horn X X X Increased numbers of calcium channels Increased calcium influx X Injury stimulates production of calcium channel Speaker’s Notes One of the mechanisms by which pain sensitivity is increased in neuropathic pain involves an increase in the production of the α2δ subunit of calcium channels. This results in the transportation of greater numbers of calcium channels to the nerve terminals in the dorsal horn, and a subsequent increase in neuronal excitability. Recent studies suggest α2δ ligands counter this effect by modulating calcium channel trafficking through binding to the α2δ subunit of calcium channels and inhibiting calcium channel transport. Reference Bauer CS et al. The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. J Neurosci 2009; 29(13): X Increased neuronal excitability INCREASED PAIN SENSITIVITY X Nerve injury Note: gabapentin and pregabalin are α2δ ligands Bauer CS et al. J Neurosci 2009; 29(13):

45 Adverse Effects of a2d Ligands
System Adverse effects Digestive system Dry mouth CNS Dizziness, somnolence Other Asthenia, headache, peripheral edema, weight gain Speaker’s Notes The most common adverse effects experienced with α2δ ligands such as gabapentin and pregabalin are dry mouth, dizziness, headache, weight gain, peripheral edema, asthenia and somnolence. Reference Attal N, Finnerup NB. Pharmacological management of neuropathic pain. Pain Clinical Updates 2010; 18(9):1-8. α2δ ligands include gabapentin and pregabalin CNS = central nervous system Attal N, Finnerup NB. Pain Clinical Updates 2010; 18(9):1-8.

46 How Antidepressants Modulate Pain
Brain Inhibiting reuptake of serotonin and norepinephrine enhances descending modulation Perception Ascending input Descending modulation Ectopic discharge Nerve lesion Speaker’s Notes The main analgesic effect of antidepressants is thought to occur by increasing the amounts of serotonin and noradrenaline available in the synaptic clefts at the spinal and supraspinal levels, and thereby enhancing the inhibitory effects of the descending modulatory pathways. It is interesting to note that at therapeutic concentrations, antidepressants have very little analgesic effect on nociception, suggesting they may help “normalize” the function of an altered pain system rather than inhibiting pain transmission. Reference Verdu B et al. Antidepressants for the treatment of chronic pain. Drugs 2008; 68(18): Transmission Glial cell activation Nociceptive afferent fiber Spinal cord Verdu B et al. Drugs 2008; 68(18):

47 Adverse Effects of Antidepressants
System TCAs SNRIs Digestive system Constipation, dry mouth, urinary retention Constipation, diarrhea, dry mouth, nausea, reduced appetite CNS Cognitive disorders, dizziness, drowsiness, sedation Dizziness, somnolence Cardiovascular Orthostatic hypotension, palpitations Hypertension Other Blurred vision, falls, gait disturbance, sweating Elevated liver enzymes, elevated plasma glucose, sweating Speaker’s Notes The most common adverse effects of TCAs include dry mouth, constipation, urinary retention, sweating, dizziness, blurred vision, palpitation, orthostatic hypotension, drowsiness and sedation. Other adverse effects include cognitive disorders, confusion, gait disturbance and falls, particularly in the elderly. The most frequently experienced adverse with SNRIs include dry mouth, constipation, diarrhea, nausea, reduced appetite, sweating, dizziness and somnolence. Rare adverse effects include elevated liver enzymes, plasma glucose levels and blood pressure. Reference Attal N, Finnerup NB. Pharmacological management of neuropathic pain. Pain Clinical Updates 2010; 18(9):1-8. CNS = central nervous system; TCA = tricyclic antidepressant; SNRI = serotonin-norepinephrine reuptake inhibitor Attal N, Finnerup NB. Pain Clinical Updates 2010; 18(9):1-8.

48 IASP: Pharmacological Treatment for Fibromyalgia
Level 1 A Amitriptyline Duloxetine Milnacipran Pregabalin Level 2 A Cyclobenzapine Fluoxetine B Gabapentin Speaker’s Notes A large number of drugs and interventions have been tested in controlled trials for their efficacy in fibromyalgia and meta-analyses have been written on most of these interventions. Some antidepressants are effective in fibromyalgia; they reduce pain, fatigue, and depression and improve sleep and quality of life. However, not all antidepressants affect these symptoms equally, and overall effect sizes are small. Nonetheless, even moderate reductions in pain may lead to considerable increases in quality of life. A meta-analysis of trials with gabapentin and pregabalin also showed effects on reduction of pain, improved sleep, and quality of life. In a comparison of duloxetine, milnacipran and pregabalin, the three drugs were found to be superior to placebo, except for duloxetine for fatigue, milnacipran for sleep disturbance, and pregabalin for depressed mood. Thus, which drug to start with is an individual choice, depending on the patient’s symptoms, comorbidities and preferences. There is weaker evidence for the effect of some other drugs, such as tramadol, and for some drugs there is good evidence that they are not effective. It must be noted that comorbid depression is not specifically treated by some of the agents mentioned or in the doses given for fibromyalgia. Thus, depression may have to be treated separately. This slide lists drugs that have been shown to have positive effects on fibromyalgia in randomized controlled trials. Level 1 evidence refers to an individual randomized controlled trial, while level 2 refers to systematic review of cohort studies or low-quality randomized controlled trials or individual cohort study or low-quality randomized controlled trial. Reference Sommer C. Fibromyalgia: a clinical update. Pain Clinical Updates 2010; 18(4):1-4. B Paroxetine Tramadol IASP = International Association for the Study of Pain Sommer C. Pain Clin Updates 2010; 18(4):1-4.

49 Discussion Question how would you integrate the concepts discussed today into a concrete treatment plan for a patient with fibromyalgia? Speaker’s Notes Ask the question shown on the slide to participants to stimulate discussion.

50 Core Treatment of Fibromyalgia
Confirm diagnosis Identify important symptom domains, their severity and level of patient function Evaluate for comorbid medical and psychiatric disorders Assess psychosocial stressors, level of fitness and barriers to treatment May require referral to a specialist for full evaluation Speaker’s Notes The steps involved in the core treatment of fibromyalgia are depicted on this slide. Treatment begins with the confirmation of the diagnosis and identification of important symptom domains and their severity (e.g., pain, sleep disturbance, fatigue) and level of function. Patients should then be evaluated for comorbid medical and psychiatric disorders (e.g., sleep apnea, osteoarthritis, depressive or anxiety disorders); some patients may require referral to specialist for a full evaluation. It is important to assess patients’ psychosocial stressors, level of fitness, and barriers to treatment and to provide education about fibromyalgia. Treatment options should then be reviewed with the patient and therapy initiated based on the patient’s presentation and evidence-based guidelines. References Arnold LM. Biology and therapy of fibromyalgia. New therapies in fibromyalgia. Arthritis Res Ther 2006; 8(4):212. Goldenberg DL et al. Management of fibromyalgia syndrome. JAMA 2004; 292(19): Provide education about fibromyalgia Review treatment options Initiate therapy based on patient’s presentation and evidence-based guidelines Adapted from: Arnold LM. Arthritis Res Ther 2006; 8(4):212; Goldenberg DL et al. JAMA 2004; 292(19):

51 Overview of Fibromyalgia Management
Confirm fibromyalgia diagnosis Educate the patient Collaborate with patient to prioritize individual treatment goals Develop treatment plan reflecting patient’s priorities and preferences At follow-up visits evaluate: Progress towards treatment goals Physical activity Use of self-management techniques Medication efficacy and adverse effects Comorbidities Adjustments to treatment plan Maintain focus on progress over time vs. daily ups and downs Pharmacotherapy Non-pharmacological therapy Treatment of comorbid conditions Speaker’s Notes This slide provides an overview of the management of fibromyalgia. As treatment progresses, it is important to evaluate progress towards treatment goals, level of physical activity, use of self-management techniques, medication efficacy and adverse effects, comorbidities at each follow up visit and to make adjustments to the treatment plan accordingly. It is preferable to focus on the patient’s progress over time as opposed his or her daily ups and downs. Reference Arnold LM et al. A framework for fibromyalgia management for primary care providers. Mayo Clin Proc 2012; 87(5): Identify other health care providers who can work with you to care for patient Identify community resources for self-management Adapted from: Arnold LM et al. Mayo Clin Proc 2012; 87(5):

52 Fibromyalgia: Medication Is Just One Part of the Treatment Approach
Revise formating Fibromyalgia: Medication Is Just One Part of the Treatment Approach NOT shown to be effective or recommended: Pharmacological treatment Non- pharmacological treatment Opioids Benzodiazepines NSAIDs Magnesium Vitamin B1 Hormonal agents (thyroxine, DHEA, melatonin, calcitonin) 3 medications approved by the FDA: Pregabalin Duloxetine Milnacipran Aerobic exercise Cognitive behavioral therapy Strength training Acupuncture Hypnotherapy Biofeedback Balneotherapy Massage therapy Behavioral therapies, such as relaxation Transcranial magnetic stimulation? Speaker’s Notes Fibromyalgia is a chronic condition, not a progressive disease. It can, however, greatly reduce the quality of life of those who suffer from this condition. Pharmacologic treatment of fibromyalgia involves targeting a variety of symptoms, often with medications from multiple classes. However, medication is just one part of the treatment approach and non-pharmacological therapy can be very important. References Häuser W et al. Review of pharmacological therapies in fibromyalgia syndrome. Arthritis Res Ther 2014; 16(1):201. Fitzcharles MA et al. Classification and clinical diagnosis of fibromyalgia syndrome: recommendations of recent evidence-based interdisciplinary guidelines. Evid Based Complement Alternat Med 2013; 2013:528952 Sumpton JE, Moulin DE. Fibromyalgia. Handb Clin Neurol 2014; 119: DHEA = dehydroepiandrosterone; FDA = Food and Drug Administration; NSAID = non-steroidal anti-inflammatory drug Häuser W et al. Arthritis Res Ther 2014; 16(1):201; Fitzcharles MA et al. Evid Based Complement Alternat Med 2013; 2013:528952; Sumpton JE, Moulin DE. Handb Clin Neurol 2014; 119:

53 Key Messages Up to 15% of adults may experience central sensitization/ dysfunctional pain, with 2–5% of adults suffering from fibromyalgia Central sensitization/dysfunctional pain is hypothesized to be a result of persistent neuronal dysregulation or dysfunction Many patients with central sensitization/dysfunctional pain syndromes such as fibromyalgia also suffer from poor sleep, fatigue, anxiety and mood disorders Multimodal therapy including both non-pharmacological and pharmacological components should be used to target symptoms of fibromyalgia Speaker’s Notes This slide can be used to summarize the main points of this presentation.


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