Objectives

Chronic pain and Fibromyalgia • Review clinical presentation and criteria for classification of FMS

• Discuss current view on FMS pathogenesis Lena Galimova MD, FRCPC January 2017 • Outline current treatment approach

Classification of soft tissue pain Epidemiology Syndromes  10% of general population reports chronic Local musculoskeletal wide spread pain as a major  Bursitis (subacromial, olecranon, trochanteric, anserine) health problem in the Western world.  Tenosynovitis (Biceps, supraspinatus, Achilles)  The prevalence of fibromyalgia is reported to be 3  Enthesopathies (lateral and medial epicondylosis) to 5 % Regional  The prevalence of myofascial pain syndrome  Myofascial pain syndrome  Complex regional pain syndrome (type I and II) varies from 21% (orthopedic clinic) to30% (general medical clinic) Generalized  Fibromyalgia syndrome  85 to 90% of patients presenting to specialty pain  Chronic fatigue syndrome management centers.  Hypermobility syndrome

FMS challenges

Fibromyalgia is a common, • Not clear etiology and therefore difficult to treat multidimensional disorder of • All symptoms are subjective unknown etiology with complex • Absence of objective evidence of tissue pathology symptomatology and relatively poor • There are no objective physical findings • Absence of reliable technology of pain treatment outcomes measurement • Absence of a gold standard confirmatory test

1 Case #1 Case #1

16y.o. female complains of chronic wsp associated with migrating paresthesia, body stiffness, interrupted non-restorative sleep, decreased concentration, chronic headaches, decreased endurance and often disproportional to exertion fatigue. Examination revealed diffused tenderness on superficial palpation without prominent bony deformities, muscle atrophy Her pain is aggravated by increased physical activity, stress, cold weather and sleep deprivation. and sings of acute synovitis. 18/18 characteristic for FMS Te Ps She is a grade 10 student with high academic performance. were identified. She gave up her sport activities and more often misses her school due to Neurologic and MSK examination did not reveal abnormality. increased pain and fatigue. PMH: recurrent ear infection in early childhood, ankle injury resulted in CRPS, Osgood-Shlatter disease. Extensive work up ruled out systemic diseases and psychiatric disorders.

Case #2

•A 35y.o.psychiatric nurse was rear ended in MVA 2 years ago.She sustained a whiplash type injury resulted in posterior neck and shoulder blade pain. •Work-up included C-spine MRI- no abnormality identified; Dx cervical facet joints blocks produced no pain relief. •Since the time of injury pain gradually spread and involved entire spine, buttocks, knees and upper arms.

Case #2

•Blood work included CBC, ESR, renal, hepatic, thyroid fn, B12 did not reveal abnormality. •PMH: migraines, growing pains, IBS. •On examination, widespread diffuse tenderness, 14/18 Teps and tender taut bands in upper trapezius and levator scapulae muscles were identified. Cervical spine ROM was restricted in lateral bending and flexion. There were no MSK or neurologic abnormalities other than thoracic scoliosis.

2 Case#3 Case#3 •A 36 y.o. farmer, mother of 3 presented with a 3 year history of wsp associated with multiple joint swelling,stiffness,disturbed sleep and fatigue. •Examination revealed diffuse tenderness, presence •10 years ago she was diagnosed with RA. Her arthritis was controlled by COX-2 inhibitor and Methotrexate. of 13/18 Teps, Trps in several shoulder blade muscles and slightly restricted cervical spine and •Despite a successful treatment of RA, she noticed that her chronic intermittent neck, shoulder blade,hands,wrists pain shoulders ROM. gradually spread to whole back, LEs and became constant. It was more prominent in the neck and shoulder blade area and •There were no signs of acute synovitis or often fluctuated in intensity. neurologic deficit.

Highlights of FMS History Highlights of FMS History

• 1904 a paper describing fibrositis was • 1977 Dr.Hugh Smythe discovered and classified written by Sir William Gowers 18 Teps in specific areas of the body in fibrositis pts.These Teps were in the same areas as those • 1915 Llewelly and Johns published a book identified by Dr. Moldofsky. describing fibrositis • 1981 A paper regarding Primary Fibromyalgia • 1975 Dr.Harvey Moldofsky discovered pts written by Dr.M.B. Yunus in Arthritis and deprived of stage 4 sleep developed tender Rheumatism Jornal. points in symmetrical locations in the same • 1990 Drs. F. Wolf, H. Smythe, M. Yunus, R. areas of the body Bennet, et al established the ACR Criteria for the classification of FMS • 1992-Present over 2,000 published papers on FMS research

FMS FMS Highlights

• Common, affects 2-4% of the US population • Occurs worldwide and has no specific • Common MSK disorder seen by rheumatologists ethnic predisposition • Extensive studies shown FMS pts do not have • Occurs in absence (primary) or presence of arthritis other conditions (SLE, RA, MPS) • 85-90% of the patients are women • Often associated with IBS(41.8%), • The most common age at presentation of 40 to 60 dysmenorrhea, endometriosis, TMJ pain, years migraines(45%),CSS, anxiety and depression(40-60%)

3 Typical Patient with FM

• Pain -few years, ill defined, flu like, not on top of the world • Energy - mostly poor • Sleep - disturbed • Mood - frustrated, angry, resentful, depressed, anxious • Reduced activity • Cognitive impairment

Exam is normal apart from tenderness

The ACR Criteria For Fibromyalgia established in 1990 1. History of widespread pain for at least 3 months in 4 quadrants of the body along with axial skeletal pain 2. Pain at 11 or more of 18 designated muscle- tendon sites called “tender points” 3. Appropriate rule/outs Note: Tender points are sites that are normally more tender i.e. sensitive to pressure

Clinical Fibromyalgia Diagnostic Criteria – Part 1 Symptom Severity Score (SS score) – Part 2a

To answer the following questions, patients should take into Indicate your level of symptom severity over the past week using the following scale. consideration how you felt the past week, while taking your current therapies and treatments, and Fatigue exclude your pain or symptoms from other known Waking unrefreshed Cognitive symptoms illnesses such as arthritis, Lupus, Sjogren’s, etc. 0 = No problem 0 = No problem 0 = No problem Check each area you have felt pain in over the past week. 1 = Slight or mild problems; 1 = Slight or mild problems; 1 = Slight or mild problems; Shoulder girdle, left Lower leg left 2 = Moderate; considerable generally mild or intermittent generally mild or intermittent generally mild or intermittent Shoulder girdle, Lower leg right 2 = Moderate; considerable right Jaw left problems; often present and/or at problems; often present and/or 2 = Moderate; considerable moderate level Upper arm, left Jaw right a moderate level at problems; often present and/or at Upper arm, right Chest 3 = Severe: pervasive, continuous, 3 = Severe: pervasive, continuous, a moderate level Lower arm, left Abdomen life disturbing problems life disturbing problems 3 = Severe: pervasive, continuous, Lower arm, right Neck life disturbing problems Hip (buttock) left Upper back Hip (buttock) right Lower back Upper leg left None of these Upper leg right areas Tally your score (not the number of checkmarks) and enter it here ______.

Count up the number of areas checked and enter your Widespread Pain Index or WPI score score here ______.

4 What Your Scores Mean Symptom Severity Score (SS score)- Part 2b A patient meets the diagnostic criteria for fibromyalgia if Check each of the following OTHER SYMPTOMS that you have experienced over the past week? the following 3 conditions are met:

1a. The WPI score (Part 1) is greater than or equal to 7 Muscle pain Nervousness Loss/change in taste Irritable bowel syndrome Chest pain Seizures AND the SS score (Part 2a & b) is greater than or equal to 5 Fatigue/tiredness Blurred vision Dry eyes Thinking or remembering problem Fever Shortness of breath OR Muscle Weakness Diarrhea Loss of appetite Headache Dry mouth Rash 1b. The WPI score (Part 1) is from 3 to 6 AND the SS Pain/cramps in abdomen Itching Sun sensitivity Numbness/tingling Wheezing Hearing difficulties score (Part 2a & b) is greater than or equal to 9. Dizziness Raynauld’s Easy bruising Insomnia Hives/welts Hair loss Depression Ringing in ears Frequent urination 2. Symptoms have been present at a similar level for at Constipation Vomiting Painful urination least 3 months Pain in upper abdomen Heartburn Bladder spasms Nausea Oral ulcers

Count up the number of symptoms checked above. Enter your score for Part 2b here _____. If you tallied: 3. You do not have a disorder that would otherwise explain the pain. 0 symptoms Give yourself a score of 0 Now add Part 2a AND 2b scores, and enter ____.

1 to 10 Give yourself a score of 1 This is your Symptom Severity Score (SS score), which can range from 0 to 12. 11 to 24 Give yourself a score of 2 Wolfe F, et al. Arthritis Care Res 62(5):600-610, 2010.

25 or more Give yourself a score of 3

What Can Mimic FM? What Can Mimic FM?

• Multiregional Myofascial pain (MFP) • Psychiatric disorder • Endocrine disturbances – Depression, borderline personality, drug seeking, – Hypothyroidism, primary hyperparathyroidism, somatization vitamin D deficiency • Drugs • Neurological disorders – Statins, aromatase inhibitors, antiepileptics – Multiple sclerosis, myasthenia gravis, polyneuropathy • Other medical conditions • Musculoskeletal disease – Early stages of rheumatoid arthritis, systemic lupus – Sleep disorders: Sleep apnea, restless legs syndrome erythematosus, psoriatic arthritis, ankylosing spondylitis, – Infections: HIV / HCV polymyositis and polymyalgia rheumatica, hypermobility – Malignancy: Multiple myeloma syndrome

Jain AK et al. J Musculoske Pain 2004; 11:3-107. Jain AK et al. J Musculoske Pain 2004; 11:3-107.

Fibromyalgia is a disorder of enhanced pain sensitivity • It is a fundamentally different type of pain syndrome in which pain is -Not due to tissue damage or inflammation -Not due to damage to or lesion of the nervous system -Often accompanied by fatigue, disturbed sleep,mood disorders,TMJ disorder,RLS,est. • FMS pain is likely due to an abnormal responsiveness or function of the nervous system

Woolf CJ. Ann Intern Med.2004;140:441-451

Lautenbacher S et al.Pain. 1994;59:45-53

5 FMS Abnormalities on Pain processing in Fibromyalgia Neuroimaging • Patients demonstrate a normal “detection Mountz JM, Bradley LA, et al. Arthritis Rheum.1995;38:926-938 threshold” to sensory stimuli, but a Abnormalities of regional cerebral blood flow in decreased “noxious threshold” the thalamus and caudate nucleus are associated in low pain threshold levels in women with FMS • It includes pressure, heat, electrical Conclusion. The findings of low rCBF and stimulation, noise, cold, est. generalized low pain thresholds support the • The decreased noxious threshold is not hypothesis that abnormal perception in women limited to tender points with FMS may result from a functional Lautenbacher S et al.Pain. 1994;59:45-53 abnormality within the CNS

Functional MRI Evidence of Augmented Pain Processing in FMS

• Level of blunt pressure needed to evoke moderate pain in FMS patients is about half the level needed in control subjects • Both patients and control subjects show similar levels of increased activity in brain regions known to be involved in pain processing • When the lower pressures delivered to patients are delivered to control subjects, there was minimal activation • These results using psychophysical and fMRI methods consistent with a general centralized augmentation of mechanical pain sensitivity in FMS • Gracely RH, Pezke F,Arthritis Rheum,2002;46:1333-1343

Neurotransmitter Effects on Pain Processing1,2 FMS Abnormalities on Neuroimaging

Facilitation Inhibition

Proton magnetic resonance spectroscopy • Substance P Descending anti- revealed changes in glutamate and • Glutamate and EAA nociceptive pathways glutamine in insula which correlated with • Serotonin (5HT2a,3a) + - •Norepinephrin symptom improvement with FM treatment • Neurotensin •Serotonine (5HT1a,b) • Nerve growth •Opioids Harris RN, Sundgren PC,et al. Program and abstracts of the ACR 71st Annual factor •GABA Meeting; November 6-11,2007;Boston,Massachusetts.(Abstract#714) •Cannabinoids •Adenosine

1. Abeles AM, et al. Ann Intern Med. 2007;146(10):726-734; 2. Staud R. Arthritis Res Ther. 2006;8(3):208-214.

6 Etiology? Neurotransmitters in FMS

• Substance P -Elevated in CSF -May play a role in central pain sensitization along with pronociceptive EAA acting at the NMDA receptors • Serotonin(5-HT) and NE -Evidence of dysfunction in both serotonin and NE 5-HT and NE mediate endogenous pain pathways via inhibitory pain pathways in the brain and spinal cord

Russell IJ et al. Arthritis Rheum.1994;37:1593-1601 Watkins LR et al Brain Res.1994;664:17-24 Russell IJ et al.J Rheumatol. 1992;19:104-109. Yunus MB et ai. J Rheumatol.1992;19:90-94

Endocrine Findings in Fibromyalgia Syndrome

Several endocrine axes have been shown to be dysfunctional in subsets of pts, but etiology of the observed abnormalities is still uncertain • Decreased 24-hour urine free cortisol • Loss of normal diurnal fluctuation of cortisol • Exaggerated ACTH response to both CRH and hypoglycemia • Low total basal plasma cortisol with normal basal free cortisol • Normal cortisol response to ACTH challenge • Delayed ACTH release after interleukin-6 administration • Decrease response of thyroid hormones and TSH to TRH • Decreased insulin-like growth factor-1 (IGF-1) • Decreased growth hormone (GH) • GH response to stimulation studies: both normal and increased in several studies using different agents for stimulation • Normal nocturnal secretion of melatonin in 2 of 3 studies

Muscle Dysfunction in FMS Suggested FMS Etiological Causes • Biopsy results (Bengston, Arthritis Rheum. 1986;29:817) Decrease in high energy phosphates • Viral infection (deregulation of the • 31P NMR spectroscopy of muscle 2.5a synthetase Rnase L antiviral (Simms AM, J Med SCI. 1998;315 (6):346) No difference in phosphate energy stores compared to pathway) sedentary controls • Lack clear evidence to conclude there is a muscle • Recent research suggested a abnormality • Recent electron microscopy suggests ultra structural clinical endocanabinoid deficiency changes including increased DNA fragmentation (Russo EB,Neuroendocrinol Lett.25:31-9) (?persistent focal muscle contractions) (Sprott H, Salemi S et al, Ann Rheum Dis.2004.63:245-51)

7 Risk Factors for FMS Psychological Phenomenon

• Familial influences (the odds ratio is 8.5 for first-degree relatives) Controlled studies using standard psychologic • Associated with genetic polymorphisms in instruments have concluded: monoamine-related genes (chromosome13:HTR2A-serotonin • No greater psychologic symptoms in FMS pts than receptor 2A;chr.17:SLC6A4-serotonin transporter; chr.22-COMT) control • Autonomic nervous system abnormalities: impaired • Majority of FMS pts do not have active sympathetic response to stressors, altered resting heart rate variability psychiatric illness • Stress: some stressors may induce the production of proinflammatory cytokines which may induce behavioral • No evidence for a specific personality type for changes(exaggerated pain responses) and central monoamiergic FMS pts changes Hudson, Bailliere Clin Rheumatol, 1994 McBeth et al., Curr Rheumatol Rep, 2001 • Environmental factors Clauw DJ, Crofford L.Best Pract Res Clin Rheumatol. 2003;17:685-701. Petzke F, Clauw DJ. Curr RheumatolRep.2000;2:116-123 Maier SF. Brain Behav Immun.2003;17:69-85 Watkins LR, Maier SF. Annu Rev Psychol.2000;51:29-57

Stepwise Treatment of Fibromyalgia1

Confirm diagnosis of fibromyalgia Fibromyalgia is more than pain. Identify important symptoms domains, Therefore,management is rarely severity, and level of patient function

monotherapy Evaluate for comorbid medical and psychiatric disorders

Assess psychological stressors, May require referral to a Level of fitness, and barriers to treatment specialist for full evaluation

Arnold LM. Arthritis Res Ther. 2006;8(4):212.

Stepwise Treatment of Fibromyalgia1 (cont.)

Provide education about fibromyalgia

Review treatment options

Evidence based treatment for patients with moderate to severe pain includes trial with medication • Do not overmedicate patient Adjunctive cognitive- behaviour therapy for patients with prominent • Locus of control shifted to patient psychological stressors / difficulty coping and/or functioning • Patient must have goals Encourage exercise according to fitness level • Patient must be active participant in treatment

Arnold LM. Arthritis Res Ther. 2006;8(4):212.

8 Therapeutic Components Recent Review of Treatments in Fibromyalgia

Good evidence for: • TCAs, SNRI, analgesics, anti-epileptics • Exercise • Multidisciplinary treatment – CBT Peripheral pain – Relaxation generators – Massage – Acupuncture

Fibromyalgia: Pharmacological Strength of Evidence – Options (RCTs) Non-pharmacologic Therapies

Strong Evidence  Aerobic exercise  Cognitive behavioural therapy  TCA  Patient education  Gabapentinnoids  Multidisciplinary therapy Moderate Evidence  Strength training  SNRIs  Acupuncture  Sodium Oxybate  Hypnotherapy  Dopamine agonist  Biofeedback  Balneotherapy  Tramadol Weak Evidence  Chiropractic, manual, and massage therapy  Cannabinoids  Electrotherapy  Ultrasound

No Evidence  Tender point injections Long term narcotics  Flexibility exercise should be minimized. Adapted from Goldenberg DL, et al. JAMA. 2004;292(19):2388-2395.

What Does Not Work? A double blind, multicenter trial comparing Duloxetine vs placebo (L.Arnold, Y. Lu et al, Arthr &Rheum,2004; 9:2974-84) • MD – Misdiagnosis • Improvement on the FIQ total score (p=0.0027) – Inattentive to mood, sleep symptoms • Not significantly on the FIQ pain score – Overtreating….pills, investigations • Greater reductions in Brief Pain Inventory average pain • Patient severity (p=0.008) – No goals, wants magic pill, unrealistic expectations • Number of tender points(p=0.002) – The passive, negative patient • Improvement on FIQ stiffness score(p=0.048) – Secondary gain • Improvement in mean TeP pain threshold(p=0.002) • Financial • Improvement was regardless of baseline status of major • Social support depressive disorder • Psychological support

9 Duloxetine Study 2

DLX 60mg/d and 120 mg/d was superior to placebo in BPI average pain score, PGI-I, CGI-Severity >50% improvement on BPI at 3 &6 mos SF-36 Mental component summary(3&6 mos for 120mg; 3mos for 60mg)

Pregabalin

• Blocks neuronal excitability -binds to alpha 2 delta subunit of voltage-gated calcium channels of neurons -reduces calcium influx at nerve terminals (inhibits release of glutamate, NA, SP • Indicated for neuropathic pain (DM, PHN) • Adjunctive therapy for partial seizures

10 Pregabalin for the Treatment of FMS (Crofford LJ, Rowbotham MC,et al.Arthritis Rheum 2005;52:1264-73) Multicenter, DB, 8-week ,randomized trial compared effect of placebo with 150, 300, 450 mg/day Pregabalin on pain,sleep, fatigue, and QL in 529 FMS pts. • 450mg/d reduced the average severity of pain(p=0.001) • More pts had >50% improvement in pain(0.003) • Significant improvement in sleep quality, fatigue, and several domains of health-related QL • Dizziness and somnolence were the most common SE • Anxiety and depression scores were not significantly improved

Recent FMS RCTs

Pramipexole, a Dopamine Agonist, in Patients With FMS Receiving Concomitant Medications (Holman JH, Myers RR, Arthritis Rheum 2005;52:2495-2505) • 4.5mg @HS reduced severity of pain(p=0.008) • Fatigue (0.021) • FIQ global score (0.028) • Global status (0.002) • No significant change in BAI and HAM-d scores • Statistically significant SE (weight loss,increased anxiety)

11 Case Series Of FMS Patients Improved With Oral Cannabinoid Nabilone

Ko G, Wine W.Cronic Pain and Cannabinoids.Practical Pain Management,2005 Improvement on FIQ, VAS, Average TePs pain threshold Conclusion: Nabilone appears helpful as an adjuvant pain medication for carefully pre-screened FMS patients

Results A Randomized double-blind placebo controlled trial assessing the effect of the • No significant differences in baseline oral cannabinoid Nabilone on pain and demographics and outcome measures quality of life in patients with FMS between the two groups Skrabek RQ, Galimova L ,The Journal of Pain, Abstract,vol 8,#4 April 2007

12 Conclusion Case#1 Treatment: The first randomized control trial to demonstrate •Attended PT sessions and than was the benefit of nabilone in fibromyalgia provided with home exercise program The significant reductions in VAS for pain, FIQ •Regular sessions with a psychologist and FIQ anxiety scores seen in the treatment (CBT) group, coupled with minimal side effects, suggest that nabilone is a beneficial, well tolerated, •Tylenol ES/#3 PRN treatment option in patients with fibromyalgia •Elavil 10mg @HS •Tizanidine 8mg @HS

Case#2 Case#3 Treatment: Treatment: •Does regular stretching and •Does regular stretching exercises aquatic exercises •Celebrex 200mg BID •Flexeril 10mg @HS PRN •Elavil 25mg @HS •Ibuprofen, Tylenol#3 PRN •Tylenol #3, Flexeril 10mg PRN •Trigger point injections q6mo •TrP injections PRN •Nabilone 0.5-1.0mg @HS

Disability and Quality of Life Conclusion

• Comparable to that in other chronic diseases • FM is a real condition characterized by • Assessment of disability is a complex issue wide spread pain, chronic fatigue, • A large majority of patients can work most of the days nonrestorative sleep, psychological distress • Influenced by education, occupation, psychological distress • Abnormality of centrally mediated pain • It is important to evaluate the patient on several visits, processing has gained greater acceptance document symptoms, job description, patient attitude, • Multimodal therapy of medication, exercise, number and location Teps education and CBT is recommended for • Concomitant diseases and severe mood disorders add to optimal treatment morbidity

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