Fibromyalgia an evolving concept Robert M. Bennett, MD, FACP, FRCP, MACR Professor of Medicine and Nursing Oregon Health & Science University

3O years ago: West J Med 134: 405‑413, May 1981 “Fibrositis is a misnomer for a very common form of non-articular rheumatism. The name implies an inflammatory process in fibro-connective tissue which has never been verified”.

Fibromyalgia is the third commonest cause of chronic pain 50 100 Prevalence (%) 59.1 27.0 5.0 1.3 3.0 Low back pain Osteoarthritis Fibromyalgia Gout Rheumatoid arthritis 1Rooks DS. Curr Opin Rheumatol. 2007;19:111-117. 2Lawson K. Neuropsychiatr Dis Treat. 2008;4:1059-1071. 3Bennett RM, et al. BMC Musculoskelet Disord. 2007;8:27. 4Lawrence RC, et al. Arthritis Rheum. 2008;58:26-35. 5Helmick CG, et al. Arthritis Rheum. 2008;58:15-25.

30 years ago the cause of fibromyalgia was a puzzle Thought to be mainly a disease of muscles

The First Reference to “Fibrositis” Postulated an inflammation of fibrous tissue between muscle bundles (hence “fibrositis) Published in the British Medical Journal in 1904

Supported Gowers’ hypothesis regarding inflammation of fibrous tissue 1904 - Histologic proof of Gower’s hypothesis? Stockman R. Edinburgh Medical Journal, 1904, 15:107-116 Supported Gowers’ hypothesis regarding inflammation of fibrous tissue

1915 - The first textbook on fibrositis All unexplained symptoms were attributed to “fibrositis” (i.e. a wastebasket diagnosis) Llewellyn and Jones of Bath

A disorder of painful muscles Understanding FM 1900 – 1930s A disorder of painful muscles Nerve impulses In order to consider the pathophysiology basis of chronic pain will analyze the changes that occur at various levels of the central nervous system; namely the periphery, the spinal cord, the brain and the descending tracks from the midbrain. Peripheral tissues

Stockman’s muscle histology could never be duplicated 1904 - Histologic proof of Gower’s hypothesis? Stockman R. Edinburgh Medical Journal, 1904, 15:107-116 Stockman’s muscle histology could never be duplicated

FM was considered to be a result of psychoneurosis “Psychogenic Rheumatism” FM was considered to be a result of psychoneurosis Boland, Annals of the Rheumatic Diseases 1947;6:195-203

“It’s all in your head” “Unexplained symptoms” are often still viewed as psychogenic in origin: Somatization Hypochondriasis Masked depression etc.

First “Scientific” Study in FM Moldofsky et al. Psychosomatic Med. 37:341-351, 1975

Electroencephalogram (EEG) sleep stages Deep sleep Delta (1- 3cps) Awake/alert Alpha (8-12 cps)

Sleep disruption in healthy subjects caused pain and fatigue Abnormal EEG in sleeping FM patients Fibromyalgia Alpha + delta EEG waves Sleep disruption in healthy subjects caused pain and fatigue

1981 - First study comparing fibromyalgia patients to healthy individuals Yunus et al. Seminars Arthritis and Rheumatism 1981, 11:151-171

FM patients often have: Irritable bowel Irritable bladder Chronic fatigue Restless legs Dizziness “Fibro-fog” Cold intolerance Multiple sensitivities The common associations are shown in this a table. As many of these associated problems are potential peripheral pain generators, an important aspect of managing fibromyalgia is to eliminate release minimize their impact.

1990 - The ACR Classification Criteria Arthritis Rheum. 1990;33:160-172 American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: Report of the Multicenter Criteria Committee F Wolfe, HA Smythe, MB Yunus, RM Bennett, C Bombardier, DL Goldenberg, P Tugwell, SM Campbell, M Abeles, and P Clark In addition to defining FM, the name was changed from “fibrositis” to “fibromyalgia”

ACR defined fibromyalgia + Widespread pain ≥ 11 of 18 tender points

Publication of the ACR criteria led to an explosion of research in fibromyalgia National Library of Medicine references on fibromyalgia in 5-Year Increments 400 800 1200 1600 1980-84 1985-89 1990-94 1995-99 2000-05 2005-09

What has been found? “Central sensitization” Sensory impulses are amplified at level of spinal cord and brain in fibromyalgia patients “Central sensitization”

Evidence for central sensitization in FM Hyperalgesia / allodynia Elevated CSF levels of neurotransmitters Temporal summation (“wind-up”) Enhanced somatosensory potentials Increased activity on fMRI and SPECT scans Impaired DNIC Response to centrally acting drugs

Found that the CSF of FM patients had elevated levels of substance P 1988 - First “nervous system” study in FM Found that the CSF of FM patients had elevated levels of substance P This finding focused attention on the nervous system, and away from muscle Lumbar puncture Vaeroy et al. Pain 32:21-26, 1988

Abnormal sensory processing in FM Hyperalgesia / allodynia Elevated CSF levels of neurotransmitters Temporal summation Enhanced somatosensory potentials Increased activity on fMRI scans Impaired DNIC Response to centrally acting drugs

Functional Brain Imaging SPECT MRS PET f MRI

SPECT scan in FM patients at rest Increased brain activity in areas that are involved in pain processing Guedj E, European Journal of Nuclear and Molecular Imaging , 2007, 34:130-4.

Important new concept: the body has a mechanism for modulating pain Brain This inhibitory pain system is dysfunctional in FM patients Descending inhibition In order to consider the pathophysiology basis of chronic pain will analyze the changes that occur at various levels of the central nervous system; namely the periphery, the spinal cord, the brain and the descending tracks from the midbrain. Peripheral tissues Spinal cord

Activation of the PAG stimulates the pain inhibitory system This pain dampening system originates in a brain area called the “periaqueductal gray” Activation of the PAG stimulates the pain inhibitory system PAG Spinal cord

A disorder of sensory amplification Understanding FM 1995 - 2009 A disorder of sensory amplification In order to consider the pathophysiology basis of chronic pain will analyze the changes that occur at various levels of the central nervous system; namely the periphery, the spinal cord, the brain and the descending tracks from the midbrain. Peripheral tissues

2009 - What are “tender points” Found that FM tender points had the typical features of myofascial trigger points

What are myofascial trigger points? There are several hundred myofascial trigger point locations in the body Trigger points are tender areas in the muscle, which when pressed cause referred pain. Knowing the referral pattern of myofascial pain is helpful in the diagnosis of FM.

Understanding FM 2009 - present FM now thought to be a disorder of both peripheral pain generators and central sensitization This latest understanding of FM is crucial for planning effective treatment strategies In order to consider the pathophysiology basis of chronic pain will analyze the changes that occur at various levels of the central nervous system; namely the periphery, the spinal cord, the brain and the descending tracks from the midbrain. Peripheral tissues

What causes fibromyalgia? Not just one gene but many Environmental insults Infections Trauma Prolonged stress PTSD Disordered sleep Alpha-delta sleep Sleep apnea Hereditary influences Genes (COMT, serotonin receptor) Epigenetics (changes in gene expression) Not just one gene but many

30 years ago the cause of fibromyalgia was a puzzle Thought to be mainly a disease of muscles

30 years later - some of the puzzle is now in place sensitization Central Pain generators Genes Environment

Next speaker please

Fibromyalgia Information Foundation Spring Conference 2010 Welcome and orientation - Sharon Clark, PhD Fibromyalgia: An Evolving Concept - Robert M Bennett, MD Diagnosis and Mis-diagnosis - Atul Deodhar, MD Guided Stretch Break - Janice Holt Hoffman How Can I Help Myself? - Kim Dupree Jones, PhD How Can Medications Help Me? - Robert M Bennett, MD Roundtable: Questions and Answers - Drs Bennett, Deodhar and Jones, moderated by Dr Sharon Clark

Diagnosis and Misdiagnosis Atul Deodhar MD, FACR, MRCP Associate Professor of Medicine Medical Director, Rheumatology Clinics Oregon Health & Science University

Why do you need a specialist? To make the correct diagnosis To ‘rule out’ other causes of generalized pain To ‘rule in’ common problems that go hand-in-hand with fibromyalgia (sleep apnea, restless legs, irritable bowel, depression etc) Fibromyalgia can co-exist with other rheumatic conditions and they shouldn’t be missed either To develop a comprehensive treatment plan

How do I make the diagnosis of FM? History & Physical Examination is usually enough to make the diagnosis of fibromyalgia Blood tests & other investigations rule out other causes of generalized pain which may have different and effective treatments It is not “since they could not find anything else on blood tests, they told me I have FM”

How do I make the diagnosis of FM? FM patients usually have Generalized Pain Tenderness all over Fatigue Sleep disturbance Depression/anxiety Cognitive dysfunction Irritable Bowel Syndrome FM patients usually do not have Weight loss Joint swelling as seen in rheumatoid arthritis Major organ (kidney, heart, lungs, brain) dysfunction Abnormal lab tests

FM Symptoms Source: National Fibromyalgia Association Survey

Do I have ‘Lupus’? Do I have ‘MS’? Autoimmune disease affecting multiple organs in a specific fashion – generalized tenderness but nothing else on examination is not lupus! Over-diagnosed with positive anti-nuclear antibody (ANA) test Autoimmune disease that presents with specific neurological deficits – true weakness, sensation loss, visual loss etc. Generalized tenderness but normal neurological examination is not MS!

“My MRI scan showed Arthritis” MRI scans are extremely sensitive and show all sorts of ‘abnormalities’ which may or may not have any clinical relevance Everyone in this room has ‘spurs’, bulging discs, degenerative discs, and “arthritis” in the spine but not everyone has chronic back pain There is no direct correlation between what you find on the MRI scan and the ‘generalized pain and tenderness’ as seen in FM

Take Home Message After the age of 30, completely normal MRI scan of the spine is as rare as hen’s teeth There is poor correlation between ‘arthritis’ changes as seen on the MRI scan and patient’s symptoms

Other common causes of generalized pain Chronic hepatitis C Hypothyroidism, Hyperparathyroidism Metastatic cancer, Multiple myeloma Vitamin D Deficiency Polymyalgia rheumatica OA, RA, Sjögren’s syndrome, SLE

ACR Classification Criteria for FM Widespread body pain Pain on both left and right sides of the body Pain above and below the waist Axial pain present Pain persisting ≥3 months ≥11 of 18 tender points (painful to 4 kg pressure)

New ACR ‘Diagnostic Criteria’ for Fibromyalgia Symptom Severity Scale (0-3) Cognitive symptoms Waking Un-refreshed Fatigue Does Pt have somatic symptoms? No symptoms Few symptoms Moderate number Great deal of symptoms Widespread Pain Index Shoulder girdle, L & R Upper arm L & R Lower arm L & R Hip buttock/trochanter L R Upper leg L & R Lower leg L & R Jaw L & R Chest Abdomen Upper back Lower back Neck 0 to 9 0 to 3 0 to 19 Wolfe F. et al. Arthritis care & Research 2010;62(5):600–610

New ACR ‘Diagnostic Criteria’ for Fibromyalgia Patient can be Diagnosed as FM if they have: Widespread pain index (WPI) 7 & symptom severity (SS) scale score 5 or WPI 3–6 and SS scale score 9 Symptoms have been present at a similar level for at least 3 months The patient does not have a disorder that would otherwise explain the pain Wolfe F. et al. Arthritis care & Research 2010;62(5):600–610

Take Home Message Your doctor doesn’t have to ‘rule out’ other diseases to diagnose fibromyalgia Fibromyalgia can co-exist with other diseases such as lupus, rheumatoid arthritis etc. Be Aware: Once the diagnosis is made, there is a risk of blaming all symptoms on fibromyalgia

What else do I look for every time I see a patient with Fibromyalgia? Sleep disturbance: Sleep Apnea Syndrome Restless Leg Syndrome Depression/Anxiety/Stress Functional status, de-conditioning Irritable Bowel Syndrome I also look for signs & symptoms that do not fit

Case Report Helen H. is a frustrated 50 year old CEO of a small company who has been treated for fibromyalgia for the past 8 months. “I just hate going to see the doctor. I’m there for fibromyalgia and instead of focusing on my pain complaints, he makes me answer questions and fill out questionnaires asking about my mood, sleep, bowel habits, and headaches. Why doesn’t he just ask about my fibromyalgia?”

Was Helen’s doctor justified? FM evaluation includes assessment of pain and other conditions that occur frequently with FM Understanding the full symptom complex & its impact allows the doctor to develop an effective treatment plan Improvement may initially occur with non-pain symptoms e.g. sleep, mood etc Not utilizing non-pain conditions may result in missing the early treatment success & abandoning treatments that might eventually improve both pain & non-pain symptoms

Summary In expert hands, FM diagnosis is straight forward, and is based on history & examination Blood tests are not required to make the diagnosis, but they help rule out additional conditions with specific therapies Several other conditions can go hand-in-hand with FM, e.g. sleep, mood, bowel disturbances Be aware: New symptoms may or may not be related to FM: Don’t hesitate to ask

20 minute break and stretching with Janice Hoffmam

Fibromyalgia Information Foundation Spring Conference 2010 Welcome and orientation - Sharon Clark, PhD Fibromyalgia: An Evolving Concept - Robert M Bennett, MD Diagnosis and Misdiagnosis - Atul Deodhar, MD Guided Stretch Break - Janice Holt Hoffman How Can I Help Myself? - Kim Dupree Jones, PhD How Can Medications Help Me? - Robert M Bennett, MD Roundtable: Questions and Answers - Drs Bennett, Deodhar and Jones, moderated by Dr Sharon Clark

What Can I do for Myself? Kim Dupree Jones PhD, FNP-BC Associate Professor School of Nursing Oregon Health & Science University 57

1. Please select the most appropriate option Medications and surgery are the only effective treatments that help fibromyalgia? True False 58

2. Please select the most appropriate option The combination of medications, cognitive behavioral strategies, education, exercise, diet and physical therapy may be used to fully treat fibromyalgia. True False 59

One size does not fit all Take Home Message To maximize benefit, treatments should match specific problems or symptoms. One size does not fit all

One Size Fits All Myth Treating everyone the same Ignoring individual differences Inconsistent results Providers may have little understanding of which treatments are worth your time

Non-pharmacological treatments for FM 024 essential oil Acupuncture Aquatic exercise (deep water running) Aerobic exercise Aloe vera Amitriptyline + Stanger bath Anthocyanidins Autogenic training Balneotherapy Biofeedback Bioresonance therapy CBT Chlorella Connective tissue manipulation + ultrasound Cryotherapy (whole body) Dance/movement therapy Delta wave sleep interruption Diet ECT Education EEG-driven stimulation Electroacupuncture Electromagnetic shielding fabric Feldenkrais Flexibility exercise Guided imagery Homeopathic vellum Hot packs Hydrogalvanic therapy Hyperbaric oxygen Hypnotherapy Laser therapy Light therapy Magnetized mattress Manipulation + ultrasound Marital counseling Massage Meditation Muscle vibration Neck support Omega-3 fatty acid Operant conditioning Peripheral neurostimulation Pool exercise + education Psychomotor therapy Qigong + mindful meditation Relaxation Stress management Stretching exercise Sulphur mud baths Tender point injections TENS Transcranial direct current stimulation Valerian bath Warm water exercise Written emotional expression 56 published studies CBT, cognitive behavioral therapy; ECT, electroconvulsive therapy; EEG, electroencephalogram; TENS, transcutaneous electrical nerve stimulation.

Exercise Top 10 Principles: Treat peripheral pain generators to minimize central sensitization Minimize eccentric muscle work Choose low-intensity non-repetitive exercise Recognize the importance of restorative sleep Address obesity and deconditioning Create fibromyalgia-friendly exercise environment Be aware of balance/dizziness problems Conserve energy in daily life Reverse pain postures (stretch anterior chest/strengthen back) Start low and go slow Jones KD & Lipton G. Exercise interventions in fibromyalgia: Clinical applications from the evidence. Rheumatic Disease Clinics of North America. 2009;35 (2), 373-391. www.myagia.com

What are Cognitive Behavioral Strategies? Understanding Treatment Options/Self-Advocacy Time-based Pacing Fatigue Control Realistic Expectation/Boundary Setting Pleasant Activity Scheduling Decreasing Catastrophic Thinking & Distraction Hassett, AL & Gevirtz (2009) Nonpharmacologic treatment for fibromyalgia: patient education, cognitive-behavioral therapy, relaxation techniques and complementary and alternative medicine. Rheumatic Disease Clinics of North America.35 (2), 393-407. 1

Self-Management: Sleep Example Lifestyle Regular bed time/wake time - Get in bed when sleepy Use bed for sleep Ride the wave of pain Caffeine in am only (remember meds) Thermal Tips - Lower core temp signals sleep - Exercise, warm bath before bed Socks, moisture wicking PJs Environment - Steady room temperature Keep room dark Silicone ear plugs No TV or computer No guilt inducing exercise equipment No bills/mail Private room (no pets/spouses…) Jones, K.D., Kindler, L.L. & Lipton, G. (in press). Self-management strategies in fibromyalgia. Journal of Clinical Outcomes Management.

Diet Living Foods Diet is a raw vegan diet including vegetables roots, fruits, berries, germinated seeds, cereals, sprouts and nuts. It excludes coffee, tea, alcohol or table salt. Concerns: lack of B12, D and Calcium, boredom, difficulty with long term compliance, inability to eat restaurant or prepackaged foods. Holton, K.F. , Kindler, L.L. & Jones, K.D., & (2009). Potential dietary links for central sensitization in fibromyalgia: past reports, future directions. Rheumatic Disease Clinics of North America.35 (2), 409-420.

Eat More Fresh Food- Less Processed Foods Some food additives contribute to FM: MSG, aspartame and l-cystine: most canned soups & stocks most flavored potato chip products (tortilla chips v Doritos) many other snack or processed foods including protein shakes many frozen dinners including diet foods and diet drinks almost all US-originated fast foods, salad dressings, marinades boxed meals including a seasoning packet Hydrolyzed protein, “natural flavors/spices” on food label Look for short food labels with words you recognize (flour, oil, salt, sugar…) Dietary exotoxins and the gut as another driver of central pain. Glutamate itself is a widespread amino acid: it is found naturally in human bodies, and is found primarily in the bound form in protein-containing foods, such as mushrooms, seaweed, tomatoes, nuts, legumes, meats, and most dairy products. Kindler, L.L., Jones, K.D., & Holton, K. (2009). Potential dietary links for central sensitization in fibromyalgia: past reports, future directions. Rheumatic Disease Clinics of North America.35 (2), 409-420.

Education & Self-Help EDUCATION / EXERCISE “Understanding Fitness How Exercise Fuels Health and Fights Disease” by Kim Jones “Full-Body Flexibility For Optimal Mobility and Strength” by Jay Blahnik “Fall Proof! A Comprehensive Balance & Mobility Training Program” by Debra J Rose “The 10 Best Questions for Living with Fibromyalgia” by Dede Bonner “Beginner’s Guide to TaiChi” by Andrew Austin REST “The End of Stress as We Know It” by Bruce McEwen “Does Stress Damage the Brain?” by Douglas Bremner “The Relaxation and Stress Reduction Workbook” by Martha Davis “Managing Chronic Pain: A CBT Approach” by John Otis “30 Scripts for Relaxation Imagery & Inner Healing” by Julie T Lusk “The Breathing Book”, by Donna Farhi

Your experiences shared

Fibromyalgia is something that you have, not who you are Find Your New Baseline Individual differences requires individualized treatment: Adequate therapy of symptoms Pain Sleep disturbances Depression/anxiety Education Accessible explanation of pathophysiology Identifying and addressing your unique perpetuating factors Setting realistic objectives- Try one treatment at a time Fibromyalgia is something that you have, not who you are Van Houdenhove B, Luyten P. Customizing treatment of chronic fatigue syndrome and fibromyalgia: the role of perpetuating factors. Psychosomatics. 2008;49(6):470-477 (page 475) Van Houdenhove, Luyten. Psychosomatics. 2008;49(6):470-477.

Next speaker please

How can medications help me? Robert M. Bennett, MD, FACP, FRCP, MACR Professor of Medicine and Nursing at OHSU

HEALTH JOURNAL / By LEILA ABBOUD Staff Reporter of THE WALL STREET JOURNAL August 3,2004 Off-Label Treatments, New Drugs Target Mysterious, Debilitating Fibromyalgia Drug companies are racing to develop drugs for a highly debilitating disease that has confounded doctors and plagued patients for years. The disorder, called fibromyalgia, causes people to feel chronic pain all over their bodies and suffer from a constellation of symptoms, including sleep disturbances, fatigue and headaches. An estimated four to six million Americans have fibromyalgia. Women are seven times as likely as men to develop it. Despite the large number of people afflicted, because of the mysterious nature of the disease, there is currently no drug approved specifically to treat it.

Now there are 3 drugs that are FDA approved for the treatment of fibromyalgia

FDA Approved Medications for Fibromyalgia Pregabalin (Lyrica) Anticonvulsant FDA-approved for fibromyalgia pain at 300-450 mg/day in divided doses BID: Start at low dose and increase as needed Adjunctive therapy of partial epilepsy, neuropathic pain Duloxetine (Cymbalta) Antidepressant Balanced SNRI FDA-approved for treatment of fibromyalgia pain at 60 mg/day: Start with lower dose and increase as recommended Other indications: major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain Milnacipran (Savella) FDA-approved for fibromyalgia management at 100-200 mg/day in divided doses BID: Starting dose: 12.5 mg; recommended increase to 100 mg/day Crofford LJ. Curr Opin Rheumatol. 2008;20:246-250. Arnold LM, et al. Arthritis Rheum. 2004;50:2974-2984. Arnold LM, et al. Pain. 2005;119:5-15.

What does FDA approval mean? The drug has been thoroughly tested and is better than a placebo The adverse events are not generally very severe However, with wider use important adverse events may lead to its being withdrawn from the market As a generalization, the currently approved drugs for FM give about 30% relief of pain to about 30% of patients Approved medications are seldom tested against each other There is usually no evidence that FDA approved medications are any more efficacious than commonly used unapproved medications

Additional Pharmacotherapy Options (Off Label in USA) Gabapentin (Neurontin) Anticonvulsant Should be used in divided doses TID for optimal effect: Most will require 1200-2400 mg/day Start with lower dose, increase to minimize adverse events Dizziness and somnolence may limit tolerability Amitriptyline and related compounds Antidepressants SNRIs Multiple actions increase adverse events: Caution in the elderly and those with heart problems Additional anticholinergic, antiadrenergic, antihistaminergic, and quinidine-like effects Fluoxetine (Prozac) Antidepressant SSRI More important effects on mood than on pain: Higher doses may improve analgesic effects More serotonin-selective agents have not been effective for relief of pain Tramadol (Ultram/Ultracet) Opioid + SNRI Useful dual action: Usual dose 100 mg / bid Is not a “scheduled” drug Crofford LJ. Curr Opin Rheumatol. 2008;20:246-250.

What treatments do FM patients really use?

NFA internet survey 2005 - Interventions Effectiveness (0-10 scale) Use Prescription sleep medications 6.5± 2.7 52% Prescription pain medications 6.3±2.4 66% Resting 6.3 ±2.5 86% Heat modalities (warm water, hot packs) 6.3 ±2.3 74% Prescription antidepressants 6.2±2.8 63% Massage/reflexology 6.1 ±2.8 43% Pool therapy 6.0 ±3.0 26% Stretching 5.4 ±2.6 62% Non-aerobic exercise (stretching,yoga) 5.1±2.9 24% Relaxation/meditation 5.1 ±5.5 47% Chiropractic manipulation 5.1 ±3.0 30% Aerobic exercise 5.0±3.0 32% Trigger point injections 5.0 ±3.3 21% Bennett et al BMC Musculoskeletal Diseases 2007, 8:27

NFA internet survey 2005 - Medications Helpful (%) Ever used Use now Hydrocodone + APAP 75 44 18 Morphine 70 14 2 Oxycodone + APAP 67 32 7 MS Contin 65 5 1 Methadone 58 6 Codeine + APAP 55 47 4 Propoxyphene + APAP 54 8 Ibuprofen 51 87 36 Tramadol + APAP 50 27 Tramadol 46 13 Naproxen 39 66 20 Acetaminophen 94 35 The most helpful drugs were all “opioids” Bennett et al BMC Musculoskeletal Diseases 2007, 8:27

Rational use of medications is dependent on understanding mechanisms of their action

Neurophysiology of nerve impulse transmission Electrical Chemical Electrical

Modulation of Glutamate Release Inhibition of glutamate release Mechanism of action of anti-seizure medications Reduced output to brain

Activation of the PAG stimulates the pain inhibitory system The pain dampening system originates in a brain area called the “periaqueductal gray” and projects down to the spinal cord Activation of the PAG stimulates the pain inhibitory system PAG Spinal cord

Mechanism of action of antidepressant medications From PAG The inhibitory pain system acts at level of dorsal horn Serotonin and nor-epinephrine are main neurotransmitters Impulses arise in nuclei of brainstem Mechanism of action of antidepressant medications Reduced output to brain

Sleep Disturbance Moldofsky et al. Psychosomatic Med. 37:341-351, 1975

Disturbed Sleep Chicken or Egg? Chronic Pain Disturbed sleep

Disturbed sleep inhibits the activity of the PAG Disturbed sleep promotes pain PAG Disturbed sleep inhibits the activity of the PAG Dorsal horn

Treating disturbed sleep Practice good sleep hygiene Be evaluated for sleep disorders Medications: Amitryptyline (Elavil) Cyclobenzaprine (Flexeril) Zolpidem (Ambien) Sodium oxybate (Xyrem)

Sodium oxybate (Xyrem) Currently under review by the FDA Improvements in sleep and fatigue Also improvemed pain, stiffness and FIQ

A basic reality Contemporary medications are of some help, but seldom reduce pain by more than 30%

Understanding FM 2009 - present FM now thought to be a disorder of peripheral pain generators and central sensitization In order to consider the pathophysiology basis of chronic pain will analyze the changes that occur at various levels of the central nervous system; namely the periphery, the spinal cord, the brain and the descending tracks from the midbrain. Peripheral tissues

Pain Generators The effective treatment of peripheral pain generators is an essential component of any fibromyalgia treatment plan Osteoarthritis Inflammation Neuropathies Injuries Disc disorders Visceral pain Chronic headaches TMP syndromes Spinal stenosis Repetitive strain Endometriosis Myofascial pain

Drug side effects (Duloxetine) † 45 40 † 35 Placebo (N=120) 30 Duloxetine 60 mg qd (N=118) % of Patients 25 * Duloxetine 60 mg bid (N=116) * 20 † * 15 * * † 10 * * * * * * * 5 Nausea Diarrhea Anorexia Dry Mouth Constipation Somnolence Hyperhidrosis Feeling Jittery Nervousness Nasopharyngitis Decreased Appetite Arnold LM et al. (2005), Pain 119(1-3):5-15 94

Everything has side effects It must be all the herbal tea you are drinking

Too much serotonin N Engl J Med 2005;352:1112-20. The serotonin syndrome is an adverse drug reaction that results from therapeutic drug use or inadvertent interactions between drugs

Serotonin syndrome Cause: excessive stimulation of serotonin receptors Presentation: Agitation or restlessness Nausea, vomiting and diarrhea Confusion , hallucinations Poor coordination Racing pulse Rapid changes in blood pressure Sweating Hyper-reactive reflexes Fever Seizures Coma

Serotonin syndrome – implicated drugs In some patients combinations of the following drugs can lead to a serotonin syndrome: SSRIs: citalopram (Celexa), fluoxetine (Prozac) SNRIs: duloxetine (Cymbalta), venlafaxine (Effexor) NDRIs: buproprion (Wellbutrin) MAOIs: isocarboxazid (Marplan) and phenelzine (Nardil) Analgesics: tramadol (Ultram), fentanyl (Sublimaze) Anti-migraine: sumatriptan (Imitrex) and zolmitriptan (Zomig) Anti-nausea: metoclopramide (Reglan) and ondansetron (Zofran) Bipolar: lithium (Lithobid) Cough: dextromethorphan (Robitussin DM) Herbal supplements: St. John's wort and ginseng This risk depends on genetic make-up (CYP 450 genes)

Individualize drug dosing based on metabolic profiling of CYP variants 2005 - The FDA-approved AmpliChip for analysis of CYP2D6 and CYP2C19, variants of CYP450 1. Extensive metabolizers. Can be administered drug in "standard“ dosages 2. Intermediate metabolizers. Multiple drug therapy can turn in people into poor metabolizers. 3. Poor metabolizers. May develop drug accumulation and adverse reactions 4. Ultrarapid metabolizers. May experience either no effect or less-than-expected effectiveness from their drug therapy

What about the placebo effect?

A typical result in a recent treatment trial (Duloxetine) 0.0 * † -0.5 Placebo response -1.0 -1.5 Change from baseline in LS mean pain score Drug effect -2.0 -2.5 -3.0 -3.5 2 4 6 8 10 12 Week Arnold LM et al. (2005), Pain 119(1-3):5-15

The “placebo” effect is often maligned Apparently your health insurance only covers placebos Take 2 placebos and call me in the morning

The latest research has demonstrated the placebo effect’s physiology Compared the effects of an opioid and a placebo on activation of brain regions in an experimental model of pain

Placebo activation of PAG area The “placebo” effect is due to activation of the descending pain system via the PAG A placebo can be the equivalent of taking oxycodone or a similar opioid drug Pain + opioid Pain + placebo Pain alone

My final piece of advice Practice activating your PAG

2 minute stretch break

Fibromyalgia Information Foundation Spring Conference 2010 Welcome and orientation - Sharon Clark, PhD Fibromyalgia: An Evolving Concept - Robert M Bennett, MD Diagnosis and Misdiagnosis - Atul Deodhar, MD Guided Stretch Break - Janice Holt Hoffman How Can I Help Myself? - Kim Dupree Jones, PhD How Can Medications Help Me? - Robert M Bennett, MD Roundtable: Questions and Answers - Drs Bennett, Deodhar and Jones, moderated by Dr Sharon Clark

Is FM a form of depression? Dr. Jones Is FM a form of depression?

Dr. Deodhar What else could it be?

Dr. Bennett Is FM inherited?

Dr. Jones Can FM be cured?

What vitamins should I take? Dr. Deodhar What vitamins should I take?

Does the XMRV virus cause FM? Dr. Bennett Does the XMRV virus cause FM?

Should I take pain killers? Dr. Jones Should I take pain killers?

Should I move to Arizona? Dr. Deodhar Should I move to Arizona?

Should I try muscle injections? Dr. Bennett Should I try muscle injections?

Dr. Jones Should I change jobs?

Should I see a psychologist? Dr. Deodhar Should I see a psychologist?

How should I prepare for surgery? Dr. Bennett How should I prepare for surgery?

Why do I hurt more when I exercise? Dr. Jones Why do I hurt more when I exercise?

Dr. Deodhar What will happen to me?

What about drugs that are not FDA approved for fibromyalgia? Dr. Bennett What about drugs that are not FDA approved for fibromyalgia?

Thank you for attending this FIF conference These presentations are available on our website at: www.myalgia.com