FIBROMYALGIA (FM

)
FM-CFS Canada

FIBROMYALGIA FOR PHARMACISTS

Janice Sumpton BSc.Phm

TABLE

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CONTENTS
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fm-cfs.ca

Table of contents . . . . . . . . . . . . . . . . . . 1. What is Fibromyalgia? . . . . . . . . . . . . 1.1 Introduction . . . . . . . . . . . . . . . . . . 1.2 Epidemiology . . . . . . . . . . . . . . . . . . 1.3 Etiology . . . . . . . . . . . . . . . . . . . . . . 1.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . 1.5 Symptoms . . . . . . . . . . . . . . . . . . . . 1.6 Pathogenesis of FM . . . . . . . . . . . . . 1.6.1 Pain . . . . . . . . . . . . . . . . . . . . . . 1.6.1.1 Central Sensitization Theory . 1.6.1.2 Dopamine Theory A Limbic 1.7 Sleep Deprivation . . . . . . . . . . . . . . 1.8 Cognitive Dysfunction . . . . . . . . . . . 1.9 Diagnostic Imaging Findings . . . . .

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2 Management of Fibromyalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Non-Pharmacological Treatment . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1 Cognitive Behaviour Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2 Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3 Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Pharmacological Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1 Pain Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.1 Tricyclic Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.2 Selective-Serotonin-Reuptake Inhibitors . . . . . . . . . . . . . 2.2.1.3 Selective-Serotonin-Norepinephrine-Reuptake-Inhibitors 2.2.1.4 Dopamine Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.5 Pregabalin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.6 Tramadol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.7 NMDA-Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.8 Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2 Fatigue Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Herbals and Supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14 4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14 Acknowledgements: FM-CFS Canada thanks Janice Sumpton, BSc.Phm for volunteering to research and write this guide for Fibromyalgia and for giving the copyright to FM-CFS Canada. See page 6 for FM-CFS Canada contact information.
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What is Fibromyalgia?

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1 What is Fibromyalgia? 1.1 Introduction Fibromyalgia (fi-bro-my-AL-ja) is a chronic condition which causes widespread pain as it's primary feature, and fatigue in addition to many other symptoms.1 It is not an inflammatory joint disorder.2 It is an "invisible disability" since very little is visible to the public. The word fibromyalgia is derived from "fibro" (fibrous tissues including tendons and ligaments), "my" (muscles), and "algia" (pain).1 Fibromyalgia (FM) is not a waste paper basket disease. Its symptoms are very real. Ongoing research is close to procuring diagnostic tools and a better understanding of the underlying cause. Once defined, one will be closer to more specific drug therapy for FM. 1.2 Epidemiology FM affects over 6 million Americans, predominantly women between 20 and 55 years of age. It also affects men and children.3 Three studies show that 2-10% of the population have FM. This co-relates to 600,000 - 3 million Canadians.4 The London, Ontario Epidemiology study indicates that 3.3% of non-institutionalized adults have FM.5 1.3 Etiology The precise cause of FM is unknown,1,6 and likely multifactorial. FM can be triggered by a physical trauma (whiplash, spinal injury, surgery, viral illness)1,4 Some studies have shown a genetic component with a strong familial pattern.1,4 In some patients there is no obvious trigger, or sudden onset, but a slow gradual onset of symptoms.4 1.4 Diagnosis In 1990 An Expert Consensus Panel devised diagnostic criteria that was adopted by the American College of Rheumatology.1,4,6 Criteria for FM diagnosis are: a) compulsary history of widespread pain for at least three months. Pain on both sides of the body, above and below the waist, and axial pain. b) compulsary pain on palpation of at least 11 out of 18 defined tender point sites when digitally palpated with a 4kg pressure.1,4,6 Routine laboratory and X-Ray testing is usually normal.1
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What is Fibromyalgia?

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1.5 Symptoms FM patients with pain and fatigue may also experience one or more of the following; body stiffness, increased frequency of headaches or facial pain, sleep disturbances, digestive complaints (including Irritable Bowel Syndrome (IBS)), genito-urinary problems, paresthesias especially in the hands and feet, highly sensitive to cold ambient temperatures, skin complaints including dry skin , eyes and mouth, and a sensation of swelling of the extremities, chest muscle pain and shortness of breath, light-headedness and balance problems, cognitive disorders termed "fibro-fog", memory lapses and "spaciness", Restless Legs Syndrome (RLS), hypersensitivity to the environment including noise, odours, light and weather patterns, and anxiety and depression. 1,4,6 Patients may also suffer from Chronic Fatigue Syndrome (CFS).6 1.6 Pathogenesis of FM The exact cause of fibromyalgia is not known at this time.1 Increased evidence is pointing to a number of pathophysiologic differences. FM patients have a decreased amount of neurotransmitters that amplify and distort pain signals.4 Low serotonin levels,1,2,4 lead to anxiety, depression, pain, sleep disorders and smooth muscle dysfunction.2 Other hormones and neurotransmitters that are low include cortisol, thyrotropin-releasing hormone (TRH), growth hormone, dopamine, epinephrine and norepinephrine.2,6 Growth hormone is required for muscle repair and metabolism. Epinephrine and norepinephrine levels lead to erratic elevations in heart rate and blood pressure. Orthostatic hypotension (lightheadedness), constricted blood vessels and Raynaud's phenomenon may be present.2 1.6.1 Pain The neurotransmitter substance P is elevated,1,4,6 up to three times normal in the cerebral spinal fluid (CSF). 2,4,5 Substance P is responsible for the transmission of pain.2 This likely explains the increased pain sensations (hyperalgesia) by increasing pain perception, and possibly increasing inflammatory cytokines production.6 Neurokinin A (also transmits pain), N-methylD-asparate (NMDA) and the excitatory amino acids (aspartate and glutamate) also increase the responsiveness of the central nervous system (CNS) to pain. Nerve growth factor (NGF) is essential for the survival of sympathetic neurons and sensory neurons NGF is four times higher in the CSF of primary FM patients compared to controls.7

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What is Fibromyalgia?

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1.6.1.1 Central Sensitization Theory The abnormal levels of these neurotransmitters and neurochemicals increase the responsiveness of the CNS neurons, thus becoming more sensitive to stimuli and the response to these stimuli is amplified. This process is termed "Central Sensitization", defined as "an exaggerated response of the CNS (spinal cord and brain) to noxious and non-noxious stimuli"8 Central sensitization results in a stimulus that causes hyperalgesia (painful stimulus causes an exaggerated painful response), allodynia, (normally non-painful stimulus (gentle touch) becomes painful). The pain spreads to areas of the body beyond the area of stimulation, and is more sustained than normal.8 The pain may be burning, sharp, stabbing, shooting, throbbing, deep aching, tingling, a bruised feeling, widespread and exhausting.4 1.6.1.2 Dopamine Theory A Limbic Pain Disorder

The hippocampus is important in FM and the deficiency of dopamine (especially D3 ) is key.9 Chronic pain alters the Hypothalamic-Pituitary-Adrenal (HPA) axis leading to atrophy of the hippocampus. This impairs the modulation of adrenergic arousal10 Mesolimbic dopamine is the main pain fighter. Decreased dopamine causes the stimulus (pain, noise, sensations) to be more intense. FM patients show atrophic changes in their brain in areas involved with pain processing.11 1.7 Sleep Deprivation Up to 90% of FM patients have a decrease in restorative restful sleep.2 In light sleep (stages 1 and 2) the brain waves are mixed alpha waves (type when awake) and delta waves. Deepest sleep (stage 4) is 100% delta waves. FM patients continue with alpha waves throughout sleep, therefore experiencing little deep sleep. Chronic sleep deprivation causes extreme fatigue,2 and exacerbates pain. 1.8 Cognitive Dysfunction Impaired cognitive function and memory problems are referred to as "fibro fog" by FM patients. The cognitive problems increase during times of a flareup in symptoms. A decrease in neurotransmitters and deficient neurophysiology of the CNS may contribute to cognitive dysfunction and memory difficulties.2 Increased pain and decreased sleep during a "fibro-flare" also contribute.2 Park et al studied FM patients for the presence of cognitive deficits compared to controls. FM patients functioned similar to matched controls that were 20 years their senior.12
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What is Fibromyalgia?

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1.9 Diagnostic Imaging Findings Single-Photon-Emission-Computed-Tomography (SPECT) scans show decreased cerebral blood flow in areas of the brain that modulate pain perception.8 Functional-Magnetic-Resonance-Imaging (fMRI) shows very quick changes in the brain. Gracely found using fMRI and increasing pain stimulus to FM patients and controls, that FM patients showed changes in regional cerebral blood flow in structures involved in pain processing. These changes on fMRI were seen at a lower pain stimulus than the pain stimulus necessary in the patients without FM.13

With thanks once again to Janice Sumpton, BCSPhm, FM-CFS Canada seeks to freely distribute this guide to health practitioners, and most of all, pharmacists. This up-to-date guide was completed in January 2007, and will be regularly updated when new developments warrant change. Visit fm-cfs.ca to find this and other guides for health professionals.

For more information: FM-CFS Canada 99 Fifth Avenue Suite 412 Ottawa ON Canada K1S 5P5 fm-cfs.ca Charity #: 89241 7742 RR0001

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MANAGEMENT

OF

FIBROMYALGIA

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MANAGEMENT

OF

FIBROMYALGIA

There is no "magic bullet" to treat FM. Control of symptoms is currently the focus of treatment. Goals include improving deep sleep and establishing a regular exercise program.2 2.1 Non-Pharmacological Treatment Cognitive Behaviour Therapy (CBT), and exercise are the best studied nonpharmacological therapies and have shown efficacy in the treatment of FM.14 2.1.1 Cognitive Behaviour Therapy Nielson reports benefits of a cognitive behaviour approach to FM treatment.15 In 198 FM patients the largest belief changes were patients belief in increased control over pain, a decreased belief that hurt necessarily equals harm, and a decreased belief in avoidance of activity is a good approach. The coping strategies with the largest changes were the use of increased relaxation and frequency of exercise.15 2.1.2 Exercise FM patients benefit from exercise which must be introduced very slowly. Stretching and strengthening exercises are important to condition the muscles.16 Cardio-vascular exercise is very important. The patient must "goslow" and progress at their own pace.2 2.1.3 Other Improved sleep hygiene to maximize sleep,4,16 eating a healthy diet, pacing activities and education about FM are also beneficial.4 One out of three controlled studies on acupuncture in FM showed significant benefit compared to placebo.17 Massage, mineral baths, and ultrasound may provide pain relief but sustained improvement is unusual.17

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PHARMACOLOGICAL TREATMENT

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2.2 Pharmacological Treatment At present there is no cure or "magic pill" to treat fibromyalgia.1 One is left with symptom management that targets chronic pain and fatigue which are often intertwined. 2.2.1 Pain Treatments Patients with fibromyalgia have many pain features that are seen in neuropathic pain syndromes,(eg. Diabetic peripheral neuropathy and Herpes Zoster (shingles)). All of these pain syndromes are chronic in nature. There is a stimulus-dependent pain sensation accompanied by hyperalgesia/allodynia and parasthesias.18 These similarities in syndromes have led to the use of drugs to treat FM pain that have been used in shingles and diabetic pain syndromes. The target of pain control is centrally-mediated in the brain and spinal cord.18 Drugs that affect neurotransmitters, specifically serotonin and norepinephrine have been studied. 2.2.1.1 Tricyclic Antidepressants Amitriptyline, and the biologically similar cyclobenzaprine, and doxepin are the most commonly used in FM (USA data). A meta-analysis of nine controlled trials of tricyclic antidepressants (TCAs) in FM produced significantly greater effects versus placebo when assessed by patients and their physicians. Improvements were seen in pain, stiffness, fatigue and quality of sleep.16 The biggest drawback of the TCAs is side-effects, especially sedation and anti-cholinergic effects. These may be minimized by starting at a very low dose a few hours before bed, and increasing the dose as tolerated. In some cases switching TCAs eg. amitriptyline changed to a morning dose of desipramine with decreased anticholinergic sideeffects. Some patients may require a further change to imipramine at night (mid-anticholinergic effects) to eliminate daytime dizziness and nightmares that may occur with desipramine.19

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PHARMACOLOGICAL TREATMENT

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2.2.1.2 Selective-Serotonin-Reuptake Inhibitors Patients unable to tolerate TCAs may be treated with Selective-SerotoninReuptake-Inhibitors (SSRIs). Fluoxetine, paroxetine and citalopram have been studied in FM as randomized placebo-controlled trials.14 The results have been mixed. Fluoxetine and paroxetine have fared better in FM relief than citalopram.14,16,20 Citalopram has greater effects on serotonin reuptake than the older SSRIs that have some affect on norepinephrine reuptake.20 This observation has led to the study of Selective-Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs). 2.2.1.3 Selective-Serotonin-Norepinephrine-Reuptake-Inhibitors Serotonin and norepinephrine are key players in descending pain pathways. SNRIs are tolerated better than TCAs because they do not interact with cholinergic, adrenergic, histaminergic receptors, or sodium channels that are responsible for most of the TCA side-effects. 20 Venlafaxine, duloxetine ( on USA market as Cymbalta®), and milnacipran (not available on the Canadian or USA market) have shown positive results in the treatment of FM. A 12-week study in 15 patients with FM were assessed before and after treatment with 75mg venlafaxine daily. The primary outcome was the Fibromyalgia Impact Questionaire (FIQ) and pain score. Depression and anxiety were measured using the Hamilton Depression and Beck Depression scales, and Beck Anxiety and Hamilton Anxiety scales respectively. Venlafaxine significantly reduced pain ( F=14.3; p=0.0001) and disability caused by FM ( F=42.7; p=0.0001). Patient and physician rated anxiety and depression were reduced significantly.21 Duloxetine is a potent SNRI anti-depressant that has also been studied in pain syndromes. It is currently indicated by the FDA in the USA for the treatment of adults with major depressive disorder and adults with diabetic peripheral neuropathic pain.20

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PHARMACOLOGICAL TREATMENT

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The first duloxetine study in FM patients was randomized, double-blind, placebo-controlled, parallel group 12 week study of duloxetine titrated to 60mg po BID in 207 patients with or without a current major depressive disorder. In the first two weeks the dose was increased from 20mg once daily to 60mg BID. The slow titration decreased nausea and insomnia. Duloxetine patients significantly improved on the total FIQ score ( p=0.027 ), but not significantly on the pain FIQ score ( p=0.13 ). Duloxetine was significantly better in the Brief Pain Inventory average pain severity score ( p=0.008 ) and Brief Pain Inventory average interference from pain score ( p=0.004 ), number of tender points ( p=0.002 ) and FIQ stiffness score ( p=0.048 ) than placebo. Improvement was seen in patients with or without a major depressive disorder. Duloxetine was well tolerated; Some duloxetine treated patients had insomnia, dry mouth and constipation more often than the placebo treated patients ( not significantly different ). Adverse effects were described as mild or moderate in severity.22 The second duloxetine study was randomized, placebo-controlled, doubleblind parallel group 12 week study in 354 women with or without current major depressive disorder. It compared placebo to duloxetine 60mg daily versus 60mg BID. A significantly greater number of patients on duloxetine 60mg daily (41%) and 60mg BID (41%) had a = 50% reduction in the Brief Pain Inventory average pain severity score compared with placebo (23%). Overall, 60mg daily and BID had no significant difference in efficacy outcomes measured. But, only the higher duloxetine dose significantly improved tender point assessments. Higher doses may be needed to improve pressure pain thresholds.23 In conclusion, duloxetine 60mg daily or BID is effective in the treatment of FM with or without a major depressive disorder. Milnacaprin is currently marketed in Asia and Europe for the treatment of depression.16 It is a SNRI with mild inhibition of N-methyl-D-aspartate (NMDA). NMDA antagonists may inhibit or attenuate central sensitization, potentially decreasing pain in FM.20 A phase-II trial studied milnacaprin in 125 FM patients.. It was a three-month study, randomized, double-blind, placebo-controlled study. Patients were randomized to 3:3:2 to daily:BID:placebo respectively. Active doses started at 25mg daily versus 12.5mg BID and doses could be escalated up to 200mg daily. The primary end-point was pain reduction. Twice daily dosing was more effective, and patients experienced less side-effects compared to the same total daily dose given once daily. Significant decreases in pain, fatigue and morning stiffness were reported. Nausea was the most common side effect. 24

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PHARMACOLOGICAL TREATMENT

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2.2.1.4 Dopamine Agonists Dopamine agonists are approved for the treatment of Parkinson's disease. Dopamine agonists are effective in the treatment of RLS which occurs 10X more frequently in FM patients compared to normal controls (31% versus 3%). RLS symptoms have been further shown to inhibit deep sleep and lead to non-restorative sleep as experienced by many FM patients.17 Ropinirole (Requip®) has specificity to the D2 and D3 subreceptors. An open-label, four-month trial with a mean dose of 4mg QHS in 17 FM patients reported a 64% decrease in tender-point score. A second trial was randomized, placebo-controlled in 30 FM patients with doses gradually increased over 14 weeks to 8mg QHS. It showed non-statistically significant improvement in pain, tenderness, fatigue and function compared to placebo.17 Pramipexole (Mirapex®) has a stronger effect on the D3 receptor than ropinirole. Pramipexole was studied in 60 FM patients. It was a randomized, double-blind, placebo-controlled, study with every 2:1 patients receiving 4.5mg QHS pramipexole: placebo, respectively. Pramipexole patients experienced gradual and more significant improvement in measures of pain, fatigue, function, and global status at 14 weeks. The most common side-effects were transient anxiety and weight loss. No patients withdrew from the study because of inefficacy or side-effects.10 In conclusion, dopamine agonists are effective in FM since chronic pain states alter the HPA axis which impairs the modulation of adrenergic arousal. Dopamine inhibits adrenergic arousal by its affects on the hippocampus that mitigates memory, learning, stress-modulation and nociception.10 2.2.1.5 Pregabalin Antiepileptic drugs are used widely in the treatment of chronic pain conditions. Pregabalin (Lyrica®) is a gamma-amino-butyric-acid (GABA) analog.14 In Canada it is approved for neuropathic pain associated with diabetic peripheral neuropathy and post-herpetic neuralgia.25 Pregabalin works by decreasing the release of glutamate, norepinephrine and substance P. Decreases in these neurotransmitters are greatest when they are already activated, as found in FM patients. Crofford et al, studied pregabalin in doses of 150mg, 300mg, and 450mg per day in a multi-centre, double-blind, randomized, placebo-controlled eight-week trial. The group receiv

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PHARMACOLOGICAL TREATMENT

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2.2.1.5 Pregabalin (continued) ing 450mg per day significantly decreased average severity of pain compared with placebo ( p = 0.001). Significantly more in the 450mg group had = 50% improvement in pain than placebo (29% versus 13%, p=0.003). Both the 300mg and 450mg doses per day groups showed significant improvements in sleep quality and fatigue. Quality of Life measures improved in those on 450mg per day. The most frequent side-effects were dizziness (usually disappeared over time), and somnolence.26 2.2.1.6 Tramadol Tramadol is a novel analgesic with weak mu-opiod receptor agonist activity and inhibition of the reuptake of norepinephrine and serotonin.16,20 These effects may exert anti-nociceptive properties that affect ascending and descending pain pathways.20 Tramadol has been studied in 315 FM patients in a 91 day, double-blinded, placebo-controlled trial of tramadol 37.5mg with acetaminophen 325mg (Tramacet®). Patients taking 4 ± 1.8 tablets per day active drug were significantly more likely to continue therapy and have improved pain and physical function, than those taking placebo. The most common side-effects in the tramadol group were nausea, dizziness, somnolence and constipation.27 Caution in starting tramadol needs to be exercised in patients already taking SSRIs or SNRIs due to the potential of Serotonin Syndrome and reduced seizure threshold with combined therapy. 2.2.1.7 NMDA-Antagonists The N-methyl-D-aspartate (NMDA) receptor plays a role in chronic pain. Blockade of this receptor can relieve pain in FM patients.16 Amantadine, dextromethorphan and ketamine are all NMDA-antagonists. 2.2.1.8 Opioids Opioids have been used in some FM patients. They have been used with mixed results. One theory to explain their ineffectiveness in FM may be that FM patients already have increased endorphin release. Their receptors are already full.28

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PHARMACOLOGICAL TREATMENT

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2.2.2 Fatigue Treatments Disrupted and non-restorative sleep is common in FM patients. The non-benzodiazepine sedatives zopiclone and zolpidem (USA product, not currently available in Canada) have been used and may improve sleep and decrease fatigue.16,20 In patients suffering with RLS clonazepam at night can be of benefit.1 Other drug alternatives for insomnia are low-dose tricyclics, pregabalin or gabapentin which have sedative effects.20 2.3 Herbals and Supplements Very little research study of herbs and supplements in FM has been done.4 The internet is abound with therapy "cures" for FM which are very expensive and not cures. Ko GD et al, studied a topical herbal agent in FM patients. This was a onemonth, randomized, placebo-controlled pilot study. The over-the-counter product tested was 024 Fibromyalgia™ consisting of six herbal oils. These are rosemary, peppermint, camphor, eucalyptus, aloe vera, and lemon/orange. The placebo oils (peppermint oil) was identical in appearance and smell to the test product. A blinded consultant (a RN.) supplied one-half of the 153 participants with active product, the remaining with placebo. Patients were to apply Q4H PRN for pain. Statistically significant improvement in the 024 Fibromyalgia™ group was seen in the Visual Analog Scale (VAS) Worst pain, active tender points, average pain threshold, average Jamar left and right grip strength.29 024 Fibromyalgia™ works as a counter-irritant. It inhibits pain fibers at the dorsal horn of the spinal cord. Locally it inhibits the pain transmitters bradykinin, histamine and prostaglandins. 024 Fibromyalgia™ is dosed up to three sprays massaged into painful muscle areas, initially best applied at night, then applied Q8H as needed for breakthrough pain.29 024 Fibromyalgia™ is available in a 30ml spray bottle, or pre-moistened towelettes. For more wide-spread pain relief two sprays or two towelettes can be added to bath water and the patient soaks in the tub for at least 20 minutes. 024 Fibromyalgia™ is absorbed into the skin quickly. If the patient finds the scent unpleasant the product can be washed off after 20 minutes without decreasing it's effectiveness. This product is supported by FM-CFS Canada and the National Fibromyalgia Association Seal of Approval in the United States.30
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SUMMARY

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3 Summary Exciting research is in progress that is leading us to firm data as to the underlying cause of FM. This is likely to be multifactorial based on findings thus far, and the different classes of drugs that have provided symptom relief. Once the cause/s are confirmed, then more specific drug treatment can be studied and available to patients suffering from this disabling, chronic pain condition.

REFERENCES

1. FMS Monograph from http://www.fmpartnership.org/engmonog.htm 2. Peterson J. Understanding fibromyalgia and its treatment options. The Nurse Practitioner 2005;30(1):48-57. 3. National Fibromyalgia Research Association. USA. Awareness Pin Card. 4. Carruthers BM, van de Sande MI. Fibromyalgia syndrome: a clinical case definition and guidelines for medical practitioners. An overview of the Canadian consensus document.2005. ISBN: 0-9739335-1-8. 5. White KP, Speechley M, Harth M, Ostbye T. The London fibromyalgia epidemiology study: the prevalence of fibromyalgia syndrome in London, Ontario. J Rheumatol. 1999 Jul;26(7):1570-1576. 6. Shuer ML. Fibromyalgia symptom constellation and potential therapeutic options. Endocrine. 2003;22(1):67-75. 7. Giovengo SL, Russell IJ, Larson A. Increased concentration of nerve growth factor in the cerebrospinal fluid of patients with fibromyalgia. J of Rheumatology. 1999;26(7):1564-1569. 8. Yunus MB. Central sensitivity syndromes: fibromyalgia and other similar conditions, the concept for unifying. Fibromyalgia AWARE.2002;May-Aug:4145.
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REFERENCES

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9. Wood PB. Fibromyalgia syndrome: a central role for the hippocampus: a theoretical construction. J Musculoskeletal Pain.2004;12:19-26. 10. Holman AJ, Myers RR. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis and Rheumatism. 2005;52(8):24952505. 11. Wood PB. "Is fibromyalgia a limbic pain disorder" talk at the Fibromyalgia Awareness Means Everything (FAME) Conference LA California, Mar 2006. 12. Park D. et al. Cognitive function in fibromyalgia patients (Epidemiology, outcome, and treatment). Arthritis and Rheumatism. 2001;44(9):2125-2133. 13. Gracely R. et al. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis and Rheumatism. 2002;46(5):1333-43. 14. Dadabhoy D, Clauw DJ. Therapy insight:fibromyalgia---different type of pain needing a different type of treatment. Nat Clin Pract Rheumatol. 2006;2(7):364-372. 15. Nielson WR. Jensen MP. Relationship between changes in coping and treatment outcome in patients with fibromyalgia syndrome. Pain 2004;109:233-241. 16. Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment. J Rheumatol 2005;32 Suppl 75:621. 17. Holman AJ. Treatment of fibromyalgia: a changing of the guard. Women's Health.2005;1(3):409-420. 18. Offenbaecher M, Ackenheil M. Current trends in neuropathic pain treatments with special reference to fibromyalgia. CNS Spectr.2005;10(3):285297. 19. Sumpton JE, Moulin DE. Treatment of neuropathic pain with venlafaxine. Ann Pharmacother.2001;35:557-559. 20. Arnold LM. Biology and therapy of fibromyalgia. New therapies in fibromyalgia. Arthritis Res Ther.2006;8:212.
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REFERENCES

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21. Sayar K et al. Venlafaxine treatment in fibromyalgia. Ann Pharmacother 2003;37:1561-1565. 22. Arnold LM et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis and Rheumatism. 2004;50(9):2974-2984. 23. Arnold LM et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005 Dec 15;119 (1-3):5-15. 24. Gendreau RM et al. Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol. 2005;32:1975-1985. 25. Lyrica® Product Information. ©2005. Pfizer Canada Inc. 26. Crofford LJ et al. Pregabalin for the treatment of fibromyalgia syndrome. Results of a randomized, double-blind, placebo-controlled trial. Arthritis and Rheumatism. 2005;52(4):1264-1273. 27. Bennett RM et al. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med. 2003;114:537-545. 28. Clauw D, Williams D, Buchwald D, Naliboff B. Panel of Speakers-talk entitled "One disease or many?" presented at Fibromyalgia Awareness Means Everything (FAME) 2006 Conference Mar. 2006, Los Angeles, California. 29. Ko GD, Hum A, Traitses GT. Do topical herbal agents provide relief? A randomized, placebo controlled pilot study of chronic pain patients having fibromyalgia demonstrated a positive response to topical herbal agents for pain management. Paper on file. Swiss Medica. 30. 024 Fibromyalgia™ Product Information. Swiss Medica.

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