Fibromyalgia, or fibromyalgia syndrome

Transcription

1 A CLOSER LOOK AT FIBROMYALGIA AND ITS MANAGEMENT* Arthur G. Lipman, PharmD, FASHP ABSTRACT Fibromyalgia, most commonly referred to as fibromyalgia syndrome (FMS), is a functional disorder with an unclear organic cause. Although the etiology is not defined, it appears to be mutifactorial, with increasing evidence of central sensitization. Pharmacotherapy for FMS, which should be integrated with rehabilitative physical activity, is often based on open-label trials and anecdotal reports, and could be improved if the pathophysiology of FMS were more fully elucidated. This article reviews the pharmacologic options and nonpharmacologic modalities available to treat FMS and its comorbidities, and explains why both approaches are necessary for successful outcomes. It also addresses the important role of the pharmacist in referring patients to healthcare professionals with experience in treating FMS and in counseling and educating patients about appropriate medication use and side effects. (Adv Stud Pharm. 2009;6(5): ) *Based on a presentation by Dr Lipman at a roundtable held in Boulder, Colorado, on June 5, University Professor, Department of Pharmacotherapy, College of Pharmacy; Adjunct Professor, Department of Anesthesiology, School of Medicine; Director of Clinical Pharmacology, Pain Management Center, University Health Care, University of Utah Health Sciences Center; Editor, Journal of Pain and Palliative Care Pharmacotherapy, Salt Lake City, Utah. Address correspondence to: Arthur G. Lipman, PharmD, FASHP, University of Utah Health Sciences Center, 30 South 2000 E, Room 258, Salt Lake City, UT arthur.lipman@utah.edu. Fibromyalgia, or fibromyalgia syndrome (FMS), is a functional disorder, which is defined as a physiologic dysfunction with no known organic basis. 1 Functional disorders, which affect up to 15% of the population worldwide, 2 share several characteristics: they occur predominantly in females; they are frequently associated with psychiatric disorders, sleep disturbances, and neuroendocrine dysregulation; patients with one of these syndromes often meet the diagnostic criteria for some of the others; and they often but not always respond, to varying degrees, to the same therapies (eg, exercise, cognitive-behavioral therapy [CBT], and antidepressant medication). Functional disorders are generally classified as gastrointestinal (GI) or non-gi. FMS is the most common non-gi functional disorder, followed by chronic fatigue syndrome (CFS), migraine and tension headache, temporomandibular joint disorder, posttraumatic stress disorder, chronic pelvic pain, interstitial cystitis and dysuria, noncardiac chest pain, and multiple chemical sensitivity (MCS). 3 As reported in a recent study, 98% of patients with FMS (vs 39% of controls) had at least one functional GI disorder most commonly irritable bowel syndrome, functional bloating, and functional fecal incontinence as well as higher levels of somatization, obsessiveness, anxiety, and depression. 4 Although pharmacists often see patients with physical, psychiatric, and other conditions with poorly elucidated pathophysiology, it is important for them to understand that the seemingly unrelated symptom constellations that patients often complain about do, in fact, fit the definition of functional disorders. FIBROMYALGIA SYNDROME As a diagnosis of exclusion, FMS presents several 140 Vol. 6, No. 5 October 2009

2 challenges. First, the lack of specific tests to prove (or disprove ) the presence of FMS is often frustrating for patients, healthcare providers, managed care plans, and third-party payers. Second is the tendency to focus on pharmacotherapy at the expense of nonpharmacologic modalities such as patient education and rehabilitative physical activity, both of which are crucial to successful treatment. Third is pharmacotherapy itself, which is often based on open-label trials and anecdotal reports in a highly suggestible population. Pharmacotherapy could be greatly improved if the pathophysiology of FMS were more fully elucidated. A recently published hypothesis for the pathophysiology of FMS attributes the syndrome to a genetic predisposition for FMS that activates neuroendocrine, neurotransmitter, and neurosensory dysfunction, all of which produce clinical symptoms in response to triggering events. 5 CLINICAL CHARACTERISTICS AND ASSOCIATED SYMPTOMS The clinical characteristics of FMS are listed in Table 1. In 1990, when the American College of Rheumatology published criteria for the classification of FMS, muscle pain was present in all patients, followed by fatigue in 96% and insomnia in 86%, rates that are consistent with those seen today. 6 However, the low incidence of major depression reported at that time differs from the much higher rates reported more recently, due in part to cumulative changes in the definitions of various affective and anxiety disorders since As noted in an ongoing study at the University of Utah, 72% of patients with FMS had either a major depressive disorder or situational depression, yet both groups were categorized under depression (Okifuji A, Personal communication, April 2009). ETIOLOGY OF FIBROMYALGIA The precise etiology of FMS is unknown, but there is considerable evidence that physical, psychiatric, immunologic, and other factors play contributory roles. Studies implicating elevated levels of nitric oxide and peroxynitrite in the pathology of FMS, CFS, and MCS, 7 enteroviral infection of skeletal muscle, 8 Mycoplasma blood infection, 9 and dietary intake of excitotoxins such as aspartate and monosodium glutamate 10 support a physical etiology. Studies supporting a psychiatric etiology include demonstration of a higher frequency of fatigue, pain, depression, and anxiety in patients with FMS and CFS 11 and data suggesting that FMS, CFS, and MCS may qualify as a single syndrome, with a history of childhood abuse and domestic violence serving as psychological predispositions to these syndromes. 12 Similarly, the association of FMS with depressed natural killer cell counts and function, low circulating levels of immune complexes, and altered immunoglobulin levels suggest an immunologic etiology. 13 As shown in numerous neuroendocrine studies, stress plays a serious role in FMS. The hypothalamicpituitary-adrenocortical (HPA) axis is the primary mechanism for generating a stress response, and the HPA axis functions abnormally in at least some subsets of patients with FMS. 14,15 Stressors and medical conditions that may trigger FMS are listed in Table 2. Table 1. Clinical Characteristics of Fibromyalgia Pain Lightheadedness, dizziness, or syncope Fatigue Chronic insomnia Cognitive deficits; short-term memory loss Depression and/or anxiety Numbness and/or dysesthesia in hands and feet Table 2. Stressors and Medical Conditions that May Trigger Fibromyalgia Stressors Peripheral pain syndromes Infections (eg, parvovirus, Epstein-Barr virus, and Lyme disease) Physical trauma (automobile accidents) Psychological stress/distress Hormonal alterations (eg, hypothyroidism) Drugs and vaccines Certain catastrophic events (war or not natural disasters) Medical Conditions Hypothyroidism Polymyalgia rheumatica Early course of autoimmune diseases (eg, rheumatoid arthritis and lupus) Sjogren s syndrome Hepatitis C Sleep apnea Chiari malformation University of Tennessee Advanced Studies in Pharmacy 141

3 Other suggested etiologies associated with FMS include hypersensitivity to inorganic mercury and nickel, 16 thyroid hormone resistance, 17 and post-viral infection, particularly hepatitis C. 18 TREATMENT OF FIBROMYALGIA Treatment of FMS typically is multimodal, combining pharmacotherapy with nonpharmacologic modalities; interdisciplinary care often is needed. Focusing on pharmacotherapy alone to manage pain, particularly in the primary care setting, is inadequate because no single drug including the 3 that are approved for FMS is consistently effective in most patients. Nevertheless, many patients do well under a primary care physician s guidance, provided there is adequate patient education, initially gentle physical activity and conditioning, appropriate pharmacotherapy, good psychological support, and attention to the comorbidities that often confound FMS. PHARMACOTHERAPY Several agents from different drug classes including tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors, and opioids have been used in the treatment of FMS, with varying degrees of clinical efficacy and effectiveness. Of the drugs used in present-day practice, only 3 (pregabalin, duloxetine, and milnacipran) are approved in this country for FMS; they are discussed elsewhere in this publication (see the article by Jacquelyn Bainbridge, PharmD, FCCP). Other drugs that are not specifically approved for FMS are indicated for the pain or depression associated with FMS. Tricyclic antidepressants Tricyclic antidepressants are often used as initial treatment for FMS. Observations in clinical practice suggest that 25% to 50% of patients show clinical improvement initially, but continued improvement is elusive. The mechanism of action of the TCAs is believed to be blockade of norepinephrine and serotonin reuptake at the neuronal membrane, with the norepinephrine effect appearing to be more important than the serotonin effect. Amitriptyline, the most well-studied TCA in FMS, has potent anticholinergic and sedative effects (Table 3). 19 The number needed to treat (NNT) to see a 50% reduction in symptoms is between 3 and 5. By comparison, desipramine has less potent anticholinergic and sedative effects than amitriptyline (Table 3), but is comparable to amitriptyline in relieving neuropathic pain. Additionally, desipramine is more noradrenergic and has a shorter half-life (still permitting once-daily dosing at bedtime) than amitriptyline. Although amitriptyline and desipramine have not been compared in a head-to-head trial in FMS, desipramine should be considered in place of amitriptyline because of its lower risk for anticholinergic and sedative side effects. Cyclobenzaprine, an amitriptyline analog with central muscle relaxant properties, has been considered for FMS despite limited evidence of its effectiveness. It has no apparent advantage over other tricyclic compounds for most patients, and its muscle relaxant activity generally ceases after 4 to 8 days of continued use. Dependence (but not addiction) is common. Although the drug s NNT for self-reported improvement was found to be approximately 5 in a metaanalysis, 20 it might be a reasonable alternative in patients with FMS who also have intermittent muscle spasticity. Opioids Although the use of opioids in FMS is not supported by data from controlled trials, anecdotal reports claim efficacy. All healthcare professionals who work in the clinical setting have seen a small percentage of patients, perhaps 10% to 15%, who do very well on Table 3. Selected Characteristics of Amitriptyline and Desipramine Amitriptyline Relative anticholinergic effects +++ Relative sedative effects ++++ Relative norepinephrine reuptake inhibition ++ Relative serotonin reuptake inhibition ++++ Half-life (hours) Desipramine Relative anticholinergic effects + Relative sedative effects + Relative norepinephrine reuptake inhibition ++++ Relative serotonin reuptake inhibition ++ Half-life (hours) Data from Lipman Vol. 6, No. 5 October 2009

4 opioids and very poorly when these drugs are discontinued. Restarting opioid therapy is reasonable in patients who use these drugs as prescribed (ie, no unauthorized dose escalation) and are adherent to the drug regimen and other components of the plan of care. Two recently published evidence-based guidelines on opioid use in chronic noncancer pain provide guidance. 21,22 Other agents and combinations Tramadol alone and in combination with acetaminophen may be helpful in treating some patients with FMS. One randomized-controlled trial demonstrated modest clinical efficacy with no serious adverse effects in 156 women who received tramadol/acetaminophen combination tablets (37.5 mg/325 mg) up to 4 times a day and 157 women who received placebo for 91 days. 23 Tramadol is a relatively safe drug, and is not a federally controlled substance. The results of a small pilot study of naloxone, a systemic opioid antagonist, suggest that it deserves further study to determine whether it has a role in treating FMS. 24 Although the single-blind crossover study included only 10 patients, the entire cohort reported a 30% reduction in pain and other symptoms compared with those receiving placebo after treatment with low-dose (4.5 mg) oral naloxone, which must be compounded. Interestingly, patients with elevated erythrocyte sedimentation rates had the greatest reduction in symptoms in response to therapy. Other reports do not support these findings. It is too early to reach any conclusions about naloxone in FMS. Tapentadol is a new chemical entity that was recently approved for the management of acute pain; studies evaluating the drug in chronic pain are under way. Tapentadol is both a µ-opioid receptor agonist and a norepinephrine reuptake inhibitor, and its mechanism of action suggests potential in the treatment of FMS, particularly as an alternative to pure µ- agonists in patients who respond to opioids. It has not yet been studied for this indication. Although the combined use of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) often is helpful in relieving concurrent nociceptive pain in patients with FMS, there is no evidence of its efficacy in FMS per se. Clinical reports advocate the use of acetaminophen and NSAIDs in selected patients (ie, those whose pain worsens when the drugs are discontinued). Because NSAIDs are associated with an increase in blood pressure, pharmacists should counsel patients about periodic blood pressure monitoring and safe dosing of these agents. Treatment of comorbidities Treatment of FMS includes managing comorbid conditions. Options for the comorbidities that most frequently accompany FMS are outlined in Table 4. NONDRUG THERAPY Nondrug therapy is essential to the overall treatment of patients with FMS. An interdisciplinary rehabilitative approach based on the chronic pain model is the core of nondrug therapy. It consists of gentle physical activity and exercise, patient education, and CBT. The effectiveness of CBT has been documented to improve coping skills, functioning, and mood However, studies have been relatively limited, and the results have been moderate. In 2001, researchers at the University of Utah examined studies evaluating the efficacy of NSAIDs, low-dose amitriptyline, exercise, and interdisciplinary rehabilitation on the tender point count, myalgic score, pain, sleep, fatigue, and mood in patients with FMS-related problems. They found that NSAIDs were not effective at all; amitriptyline had significant positive effects on sleep, pain, and fatigue; and exercise was associated with significant reductions in tender point count and myalgic score (Okifuji A, Ashburn MA, Table 4. Symptomatic Pharmacotherapy for Comorbidities Irritable bowel syndrome Fiber, guar gum, and pitted prunes Chronic fatigue syndrome Possible use of stimulants Depression Antidepressants and psychotherapy Insomnia Very conservative use of hypnotic agents Improved sleep hygiene Anxiety Anxiolytic agents Dry/itchy eyes Artificial tears University of Tennessee Advanced Studies in Pharmacy 143

5 2001; Unpublished observations). Only the interdisciplinary approach was consistently effective across all domains. Ongoing research comparing the effect of patient education, CBT, and motivation-based emotional therapy (MET) on pain, function, and symptom coping in patients with FMS has found greater improvement in all 3 areas with MET than with traditional CBT (Okifuji A, Personal communication, April 2009). It appears that improving motivation, not just cognition, should be included in psychotherapeutic approaches for optimal outcomes. CONCLUSIONS The etiology of FMS is unclear, but it appears to be multifactorial, with accumulating evidence of central sensitization. Optimal pharmacotherapy should be based on etiology. Pharmacotherapy should not be the sole intervention in the treatment of FMS, but should be integrated with rehabilitative modalities. In addition, pharmacotherapy should not be directed to pain relief alone, but to other symptoms as well. Because no single drug is effective for the majority of patients, therapy needs to be multimodal and customized to address the patient s symptoms. Pharmacists should identify the best FMS clinicians in their communities and refer accordingly. They should also continue to educate and counsel patients with FMS about optimal medication use. DISCUSSION PHARMACOTHERAPY ISSUES Dr Strassels: Why is it that no single drug is consistently effective in most patients? Dr Lipman: That finding is based on the NNT analyses. In other words, how many patients do we have to treat with a given drug to get a 50% reduction in symptoms? We typically look for an NNT of 5 to 6, meaning that only 1 out of 5 or 1 out of 6 patients is likely to respond to any single pharmacotherapy with a 50% reduction in symptoms. The US Food and Drug Administration criterion for approving drugs for FMS is not the majority of patients responding, but a statistically significant separation from placebo. Dr Natelson: The major problem I have with TCAs is weight gain. If I prescribe a TCA for a woman who is in pain and she gains 20 pounds, the extra weight is likely to make it even more difficult and painful for her to get around. Dr Lipman: I prefer not to use amitriptyline because it has 4 times as much anticholinergic effect per milligram as desipramine, which has been shown to have comparable efficacy at equal doses in doubleblind studies of (non-fms) neuropathic pain. Although these drugs have not been tested for analgesic equivalence in FMS, it is reasonable to assume that they have similar efficacy in FMS as well. Moreover, desipramine has a far better side-effect profile than amitriptyline. The anticholinergic effect appears to be the primary cause of the side effects we are familiar with, including increased appetite leading to weight gain. Dr Natelson: The reason I use amitriptyline is for its sedative effects. Dr Lipman: Even when sleep is an issue, desipramine may be a better choice because it produces initial sedation with far less anticholinergic activity. Patients with functional pain disorders are not lying awake at night because of low blood levels of amitriptyline; they are awake because of pain. Dr Strassels: Because naloxone is taken by mouth, it seems to suggest peripheral activity. Have you seen any evidence for the peripheral antagonists themselves? Dr Lipman: The original supposition was that oral naloxone for opioid-induced constipation would act locally on the µ receptors in the gut, but the evidence does not support that. Some absorption is needed for systemic effect. Patients with functional pain disorders may have a more porous gut than healthy individuals, and that might account for the small amount of systemic absorption of naloxone that produces the peripheral effect. INTERDISCIPLINARY APPROACHES AND ALGORITHMS Dr Kirsh: Including good psychological support in the overall treatment plan for FMS is extremely important. As a licensed clinical psychologist, I can say that not all psychologists are created equal, just as not all physical therapists are the same, a point that was made in the previous discussion. In chronic pain globally, and in FMS in particular, the pharmacist needs to know the psychologist s approach to pain management before making any recommendations or referrals. I was trained at 1 of only 2 institutions in the country that focus on medically based psychology, and we feel that psychologists who are opposed to medications are doing patients a disservice. Just as you have to find the 144 Vol. 6, No. 5 October 2009

6 right doctor to treat patients with FMS, you have to find the right mental health professional as well. Otherwise, you might do more damage. Dr Lipman: Pharmacists should develop referral patterns. Once the pharmacist identifies the knowledgeable physicians in the community, those physicians can help the pharmacist identify the best mental health professionals and physical therapists for FMS. Dr Penna: Are there any widely accepted treatment algorithms? Dr Lipman: No. Individual clinicians usually devise their own. The one that Dr Natelson presented is perfectly reasonable, with the explicit caveat that the pharmacotherapy runs parallel with physical activation and psychosocial support. Dr Penna: We are dealing with a condition that is ill defined in terms of etiology and pathophysiology. The treatments are also ill defined. It reminds me of the time when lovastatin was approved and there was a lot of buzz about lipid disorders. I was at Group Health at the time, and it took us 2 years to figure out what to do about treating lipid disorders because there was no good outcomes evidence available. I remember the frustration of a family physician who said, I don t know what to do when I see a patient with a lipid disorder, but I will do something. I believe many practitioners have the same problem with FMS. It is up to the scientists working in the field to develop improved treatment approaches and algorithms that better define the approach. Dr Lipman: I think you are right. But unless we have solid evidence on which to base an algorithm and advocate its use, then by definition we may be making an error. The first thing we do at our clinic when we see a patient with FMS is a careful workup. It is very time intensive, but it is an up front cost that is costeffective in the long run. It is also important to use an interdisciplinary approach, but in today s economic climate, the first service that is being cut back by third-party payers is psychological services. Without psychologists for our patients with chronic noncancer pain, we are likely to make mistakes and use very expensive medical interventions that are not indicated or are even contraindicated. Managed care pharmacists should recognize that up front costs often can save money in the long run, and that we need good pharmacoeconomic analyses, ideally during phase IIIA clinical studies. Waiting until phase IV postmarketing studies is a problem because practice patterns often are established soon after a drug comes on the market. When evidence contrary to what physicians are used to doing emerges, pharmacists can help educate physicians about multiple reasonable approaches to effective therapy. REFERENCES 1. Functional disorders. The Free Dictionary Web site. Available at: Accessed September 15, Mayer EA, Bushnell C. Functional Pain Syndromes: Presentation and Pathophysiology. Seattle, WA: IASP Press; Gastrointestinal and non-gastrointestinal functional disorders. International Foundation for Functional Gastrointestinal Disorders. Available at: about-ibs/other-disorders/ibs-non-gi-disorders. Accessed September 15, Almansa C, Rey E, Sánchez RG, et al. Prevalence of functional gastrointestinal disorders in patients with fibromyalgia and the role of psychologic distress. Clin Gastroenterol Hepatol. 2009;7: Giamberardino MA. Update on fibromyalgia. Pain Clin Updates. 2008;16(4): Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;32: Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and post-traumatic stress disorder. Ann NY Acad Sci. 2001;933: Douche-Aourik F, Berlier W, Féasson L, et al. Detection of enterovirus in human skeletal muscle from patients with chronic inflammatory muscle disease or fibromyalgia and healthy subjects. J Med Virol. 2003;71: Endresen GK. Mycoplasma blood infection in chronic fatigue and fibromyalgia syndromes. Rheumatol Int. 2003;23: Smith JD, Terpening CM, Schmidt SO, Gums JG. Relief of fibromyalgia symptoms following discontinuation of dietary excitotoxins. Ann Pharmacother. 2001;35: Van Houdenhove B, Neerinckx E, Onghena P, et al. Daily hassles reported by chronic fatigue syndrome and fibromyalgia patients in tertiary care: a controlled quantitative and qualitative study. Psychother Psychosom. 2002;71: Ciccone DS, Natelson BH. Comorbid illness in women with chronic fatigue syndrome: a test of the single syndrome hypothesis. Psychosom Med. 2003;65: Buchwald D, Komaroff AL. Review of laboratory findings for patients with chronic fatigue syndrome. Rev Infect Dis. 1991;13(suppl 1):S12-S Crofford LJ. The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome. Z Rheumatol. 1998;57(suppl 2): University of Tennessee Advanced Studies in Pharmacy 145

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