Fibromyalgia and the Pharmacist's Role

Release Date: May 1, 2012

Expiration Date: May 31, 2014

FACULTY:

Marissa Salvo, PharmD
Assistant Clinical Professor
University of Connecticut School of Pharmacy
Storrs, Connecticut

Tara Dymon, PharmD, BCACP
Assistant Professor of Clinical Sciences
Roosevelt University College of Pharmacy
Schaumburg, Illinois

FACULTY DISCLOSURE STATEMENTS:

Dr. Salvo and Dr. Dymon have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-12-009-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To educate pharmacists about fibromyalgia, its diagnosis, and available pharmacologic and nonpharmacologic therapies in addition to providing ways pharmacists may assist patients in managing fibromyalgia.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Define fibromyalgia and describe its pathophysiology, available assessment tools, and impact on patient health.
  2. Summarize guidelines for fibromyalgia diagnosis and treatment.
  3. Discuss available pharmacologic and nonpharmacologic drug therapies for fibromyalgia treatment.
  4. Describe the role of the pharmacist in fibromyalgia management.

Fibromyalgia (FM) is a chronic pain syndrome that is associated with a variety of symptoms including widespread pain, tenderness, fatigue, and sleep disturbances.1 Additional symptoms include insomnia, problems with memory, difficulties in concentration (often referred to as the fibro fog), a feeling of tingling in the extremities, and headaches.2 More women than men have FM, with a ratioof 9 to 1.3,4 In the United States, FM affects an estimated2% to 4% of the population (~10 million individuals); however, it is believed that FM is underdiagnosed.1,4,5 Diagnosis of FM commonly occurs between ages 20and 50; however, prevalence increases with age, peakingbetween ages 70 and 79.1,3 While FM is the second (toosteoarthritis) most common condition observed byrheumatologists, only 20% of patients receive FM care from rheumatologists.1,5

PATHOPHYSIOLOGY

The exact cause of FM is unknown. However, the primary theory supports central sensitization, an overreactivity of the central nervous system, caused by a varietyof stimuli and dysregulation of the ascending and descending pain pathways.6,7 FM is also associated with reducedlevels of serotonin and norepinephrine. Because serotoninand norepinephrine are antinociceptive, low levels indicate dysregulation of pain impulses, thus resulting in hyperalgesia, increased sensitivity to pain, and allodynia, pain caused by simple touch/pressure.8,9 In addition, patients with FM have increased levels of substance P and glutamate, neurotransmitters that amplifypain impulses in the ascending pain pathway.8,10 Therefore, modulation of the identified neurotransmitters iskey to FM treatment.

Additional findings revealdisturbances in the neuroendocrine axis, particularlyas it relates to sustaining deepstage 4 sleep; alterations in the hypothalamic-pituitary-adrenal axis with low overall production of cortisol;and peripheral sensitization.11-13 A genetic link also exists, as there are frequent comorbidities.14 First-degreerelatives of FM patients have eight times the risk forFM as the general population.8 Exposure of geneticallypredisposed individuals to environmental factors (i.e.,infection, stress, trauma) may also contribute to thedevelopment of FM.15,16

DIAGNOSTIC CRITERIA

The American Medical Association first recognized thevalidity of fibromyalgia in 1987.17 In 1990, the American College of Rheumatology (ACR) published definedcriteria for the diagnosis of fibromyalgia.18 No currentlyavailable laboratory tests or imaging technology confirmsthe diagnosis of fibromyalgia; therefore, criteria are solelysymptom based. According to the 1990 ACR guidelines,patients must have pain that is chronic (>3 months) andwidespread (occuring on both theleft and right sides of the body,above and below the waist, andin the axial skeleton). The guidelines also introduce the conceptof tender points and state thatpain must be present upon palpation in at least 11 of 18 specific sites (FIGURE 1). Higher numbers of tender points are associated witha greater severity of fibromyalgia.19



Figure 1. Tender point locations.
Source: Reference 18.

Twenty years passed before newpreliminary diagnostic criteria forfibromyalgia were published by theACR in 2010.20 In the updated preliminary criteria, tender points are no longer part of the FM diagnosis. According to the authors, tender point examinations were rarely performed, and when performed were often done incorrectly. Additionally, a patient with longstanding widespread pain but only 10 tender points would not meet the original fibromyalgia definition but could indeed have fibromyalgia. The original criteria also failed to capture those patients who might have fluctuating symptoms. In the updated guidelines, the widespread pain index (WPI) replaces the tender point criteria, and the symptom severity (SS) scaleassesses differences in fibromyalgia severity. Using theWPI and SS scale, the following definition of fibromyalgia is proposed: WPI > 7 and SS > 5 or WPI 3-6 and SS > 9 (TABLES 1 and 2).20



ASSESSMENT TOOLS

In addition to the WPI and SS scale, other tools areavailable for assessing the symptoms, treatment effectiveness, and impact of fibromyalgia.

  • The Fibromyalgia Impact Questionnaire (FIQ) is a 10-question, self-administered survey used to assess fibromyalgia-related symptoms such as fatigue, pain, impairment of daily functional living, anxiety, and depression. Higher FIQ scores indicate greater levels of impairment.21
  • The Brief Pain Inventory (BPI) is available in both a long and a short form and may be used to assess pain intensity, patient perception of pain, and the impact of pain on daily living.22
  • The Patient's Global Impression of Change (PGIC) scale allows the patient to describe the change in his or her overall health status as well as in quality of life, pain, or functioning. The Clinician Global Impression of Change (CGIC) scale is similar but provides assessment from the clinician's perspective.23
  • The Short Form-36 (SF-36) health survey contains 36 validated questions to assess quality of life in patients diagnosed with musculoskeletal disorders.24

IMPACT OF FIBROMYALGIA

Despite the availability of FM guidelines, it takes an average of 5 years to accurately confirm a diagnosis. Medical providers must rely on patient-reported elements, such as history and symptoms, and the manual tender point exam.3 The subjective nature of FM is a reason for a diagnostic delay. Many patients with FM also have comorbid conditions that are not easily distinguishable from FM. Pain and fatigue, the primary FM symptoms, can overlap with symptoms of other conditions, thus further complicating the diagnostic process. Comorbid conditions include depression, irritable bowl syndrome, dysmenorrhea, and restless legs syndrome.2

A fibromyalgia diagnosis significantly influences functional capacity, potentially leading to disability and a decrease in quality of life.25 One study compared FIQ scores of patients with FM to patients experiencing other types of pain and no pain (controls). The mean total score of patients with FM was 61.2, whereas in other pain patients and controls, the mean scores were 41.6 and 21.9, respectively. This study also found that patients with FM reported a greater number of days in bed within the past 2 weeks (2.0, 0.4, and 0.3 days, respectively).26 In a review of several studies, it was found that patients with FM had similar or significantly lower SF-36 scores than patients with rheumatoid arthritis, osteoarthritis, and systemic lupus erythematosus. The results indicate worse quality of life for patients with FM compared to others with persistent pain.25

Patients with FM also have increased medical costs. In comparing costs of FM to those of osteoarthritis or no medical condition, similar costs were observed between groups diagnosed with FM or osteoarthritis; however, cost were greater compared to groups with no medical condition.26 Another study found that during the course of 1 year, patients with FM had four times as many doctor office visits and emergency room visits as those without FM. This translates into a mean cost three times greater than that of patients without FM.4

Overall, FM significantly impacts the patient, employer, and health care system. Optimizing treatment is essential to improve the patient's quality of life. In turn, improvement in quality of life will improve patient functionality, reduce disability, and decrease medical costs.

FIBROMYALGIA MANAGEMENT

Since no cure for fibromyalgia exists, the goal of FM therapy is improvement of symptoms, focusing on those that affect quality of life, such as pain, physical dysfunction, and impaired sleep. FM management includes a multimodal approach consisting of pharmacologic and nonpharmacologic therapy, complementary and alternative medicine, and patient education.27 Evidence also supports efforts of a multidisciplinary team to improve overall well-being.28

Pharmacologic Therapy

To date, there are three FDA-approved medications with an indication of fibromyalgia treatment. They include pregabalin (Lyrica), duloxetine (Cymbalta), and milnacipran (Savella).29-31 FDA approval of these medications occurred following development of the American Pain Society (APS) and European League Against Rheumatism (EULAR) guidelines.27,32 Complete drug information for pregabalin, duloxetine, and milnacipran is in TABLE 3. The following studies describe the efficacy of each agent.


tbl3

A randomized, double blind, placebo-controlled trial of FM patients (90% female) receiving duloxetine 60 mg/day with or without depression showed statistically significant improvement on the PGIC scale at 3 months in addition to a >30% reduction in the BPI. At 6 months, a statistically significant difference was noted with a >50% reduction in the BPI from baseline. This study demonstrated that duloxetine is effective for FM management in patients with or without depression.33 A similar study in women with FM found reductions in FIQ scores, BPI scores, and number of tender points and improvement in quality of life.34

In a 15-week randomized, double-blind trial of milnacipran compared to placebo, milnacipran was found to have significant improvements in PGIC status, physical function, and fatigue.35 In addition, a 6-month, randomized, double-blind trial of milnacipran compared to placebo demonstrated that milnacipran was significantly more likely to reduce pain and fatigue.36

In short-term studies, pregabalin compared to placebo produced significant reductions in mean pain scores, PGIC response, and FIQ scores.37,38 A 6-month trial found that the noted short-term improvements continued with ongoing pregabalin therapy.28

Ongoing comparison studies are necessary to assess long-term safety and efficacy of the approved FM medications. A meta-analysis, including 17 identified trials (average length of 24 weeks), compared the three FDA-approved FM medications. No significant difference was noted in an adjusted indirect comparison with respect to achieving a pain reduction of >30%; however, differences were identified in symptom reduction and side effects (TABLE 4).39 With this information in addition to drug information, selection of an agent should be individualized based on patient symptoms, concomitant medical conditions and/or medications, potential side effects, and other drug-related information (i.e., contraindications, interactions).


tbl4

Off-Label Medications

Before the FDA approval of any medications for the treatment of fibromyalgia, the APS and EULAR guidelines provided recommendations for therapy.27,32 In 2004, APS guidelines strongly supported the use of tricyclic antidepressants (TCAs) and moderately supported the use of serotonin and norepinephrine reuptake inhibitors (SNRIs), fluoxetine, tramadol, and pregabalin.27 The 2008 EULAR guidelines provided recommendations for tramadol, amitriptyline, fluoxetine, duloxetine, milnacipran, pramipexole, and pregabalin; analgesics such as acetaminophen and weak opioids were also recommendations.32

Tricyclic Antidepressants and Cyclobenzaprine: TCAs, in particular amitriptyline, were often considered as the best first-line option before FDA-approved fibromyalgia medications were available, due to effectiveness in pain reduction and ability to increase deep sleep.13 A systematic review published in 2008 by Nishishinya et al described 10 randomized, controlled trials evaluating the safety and efficacy of amitriptyline for treatment of fibromyalgia.40 A total of 615 patients with FM received amitriptyline 25 to 50 mg orally daily; the 25-mg daily dose was found to have statistically significant benefits for pain, sleep, fatigue, and global assessments by patients and physicians at 6 to 8 weeks. The effect was no longer significant at 12 weeks, however, and the 50-mg daily dose did not show significant benefits compared to placebo. Use of amitriptyline is often limited by its side effects (sedation, dry mouth, weight gain); however, nortriptyline (the active metabolite of amitriptyline) has been suggested as an alternative with fewer side effects but limited data are available to support its use in fibromyalgia. Cyclobenzaprine, which is structurally similar to TCAs without the same adverse effect profile, has also been studied for the treatment of fibromyalgia; however, it was not mentioned in the APS or EULAR guidelines. A meta-analysis of five trials including 312 patients with FM showed benefit in those treated with cyclobenzaprine 10 to 30 mg daily over placebo.41

SSRIs and SNRIs: The APS guidelines mention SNRIs as a class and cite fluoxetine as the only selective serotonin reuptake inhibitor (SSRI) for the treatment of fibromyalgia; whereas, the EULAR guidelines mention fluoxetine, duloxetine, and milnacipran as therapeutic options. Both SSRI and SNRI agents may be effective in fibromyalgia due to their ability to alter serotonin levels and provide benefits in depression, a common comorbidity in patients with fibromyalgia. Many randomized, controlled trials studied SSRIs compared to placebo and amitriptyline. SSRIs appear to be better tolerated than TCAs but have been found to be less effective than TCAs for management of fibromyalgia pain.42

In addition to the FDA-approved SNRIs duloxetine and milnacipran, venlafaxine (the first SNRI available in the United States) has also been studied for use in patients with fibromyalgia. However, due to limited data (only two small trials are available), venlafaxine is not often recommended.

Gabapentin: Structurally similar to pregabalin, gabapentin may also be an option in treating fibromyalgia. A 12-week study comparing gabapentin (1200-2400 mg/ day) in 75 patients to an equal number of patients using placebo found gabapentin to be safe and efficacious for patients with pain related to fibromyalgia, using the BPI assessment tool.43

Analgesics: Because chronic, widespread pain is central to the diagnosis of fibromyalgia, analgesics may be prescribed for patients; however, there are limited data to support their use. Nonsteroidal anti-inflammatory agents (NSAIDs) and corticosteroids have both been found to be ineffective for the treatment of fibromyalgia pain. Strong opioids may actually worsen fibromyalgia symptoms by causing drowsiness and decreased cognition. Tramadol and tramadol with acetaminophen have been shown to be more effective than placebo for pain associated with fibromyalgia, but are still not routinely recommended.13

Nonpharmacologic Therapy

Nonpharmacologic therapies are included in both the APS and EULAR fibromyalgia guidelines. APS guide lines give the strongest level of recommendation (A) to aerobic exercise, cognitive behavioral therapy (CBT), multidisciplinary therapy, and patient education. A moderate level of recommendation (B) is given to acupuncture, balneotherapy (use of therapeutic bathing), biofeedback, hypnotherapy, and strength training.27 EULAR recommendations differ significantly, giving moderate recommendations (B) to balneotherapy; weaker recommendations (C) to individually tailored exercise, physiotherapy, psychological support, relaxation, and rehabilitation; and a low level of recommendation (D) to CBT.32 While not mentioned in either set of guidelines, good sleep hygiene may also help patients with sleep disturbance-related fatigue. Therefore, patients should be encouraged to practice good sleep hygiene to minimize sleep disturbances.2

CBT is the combination of both cognitive and behavioral therapies. In the case of fibromyalgia, CBT is utilized to improve self-management.44 Cognitive therapy is used to modify maladaptive thoughts, ideally resulting in changes to both affect and behavior. For example, the thought "My pain is terrible and I'm helpless in dealing with it" may be turned into "Even if my pain becomes bad, there are things I can do to make it slightly better." Behavioral therapy is used to increase adaptive behavior through reward and decrease maladaptive behavior through punishment. By this method, patients will ideally achieve behavioral activation (increased movement/activities) and reduction in pain behaviors, and will learn techniques to relax and decrease stress. CBT has been shown in meta-analyses to be effective in depression, anxiety, and chronic pain treatment.44

Because of pain and fatigue, patients with fibromyalgia are often sedentary and may become deconditioned.35 A 2007 Cochrane review showed that strong evidence exists to support the use of exercise in managing fibromyalgia. Supervised aerobic exercise was given a "gold level" of evidence, and strength training also showed benefits.45 Pharmacists should encourage patients to engage in exercise and advise them to start slowly with an exercise plan and to enlist the assistance of a professional when starting an exercise regimen so as not to overexert themselves.

Balneotherapy has been shown to significantly improve fibromyalgia symptoms such as pain, depression, and number of tender points.46,47 There is evidence to show that pool-based exercise (such as water aerobics) may be more effective than balneotherapy alone.48

Complementary and Alternative Medicine

Some individuals utilize complementary and alternative medicine (CAM) as part of fibromyalgia treatment. While not as extensively studied and often providing varying results, CAM therapies maybe considered beneficial for some patients. For example, with small studies and a varying number of acupuncture sessions, no definitive conclusions can be drawn on the role of acupuncture in FM treatment.49 Pharmacists should encourage patients who choose to use acupuncture to seek a certified professional who is familiar with how acupuncture may impact FM. In addition to acupuncture, CAM therapies include massage therapy, spinal manipulation, dietary supplements, and t'ai chi, among others.5,13

Studies assessing the effectiveness of dietary supplements in FM are also limited.5,2 Furthermore, it is important for pharmacists to discuss with patients the potential role of dietary supplements and their regulation by the FDA.2 It is wise to encourage patients to seek a medical provider's input on dietary supplement use prior to beginning therapy.

THE PHARMACIST'S ROLE IN MANAGING FIBROMYALGIA

Pharmacists can assist FM patients in a variety of ways to better manage their condition. For patients taking prescription medications, it is the pharmacist's duty to ensure safe use of the medication. Pharmacists should ensure that patients receive a medication guide with each fill of the FDA-approved FM medications and also when required with other off-label medications for FM treatment. In addition, pharmacists need to educate patients on correct medication use, as dose titrations maybe required; potential side effects; interactions (intervening as necessary); monitoring parameters; and additional counseling points (TABLE 3). Pharmacists are excellent resources to answer a patient's drug therapy questions.

Pharmacists should not only discuss medication use with FM patients, but also discuss FM and its management. FM is a chronic and complex condition that often exists with a number of other medical conditions, all of which will impact the patient's quality of life. Pharmacists can recommend resourses (TABLE 5) for the patient to learn more about FM.


Pharmacists are a valuable resource to patients when assessing nonpharmacologic therapy for FM. Pharmacists can advise patients on the subject of exercise, especially with regard to education on its benefits and encouragement to start slowly and enlist the help of a professional if necessary. Pharmacists may also counsel patients who complain of sleep disturbances about proper sleep hygiene. Important points include keeping a regular sleep schedule, avoiding stimulants such as caffeine and spicy meals later in the day, regularly engaging in exercise but not near bedtime, avoiding naps during the day, and creating a restful environment by making the bedroom dark, quiet, and cool.

Pharmacists should inquire about CAM use due to potential interactions of dietary supplements with prescription medications. Pharmacy records should be updated accordingly to ensure safe use of all therapies. If a patient is interested in utilizing CAM, pharmacists can research and evaluate available evidence to assist patients in making an informed decision. In addition, pharmacists can also provide details regarding their regulation.

Finally, pharmacists should work as a member of the patient's health care team. Pharmacists can identify and explore medication nonadherence. With frequent patient contact, pharmacists can also assess response to therapy and communicate with medical providers regarding drug therapy. Pharmacists may also work with patients to develop realistic goals to better manage FM and its symptoms.

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