An FM Pharmacy Treatment Update for Pharmacists, Patients, & Physicians

This FM research update, reproduced with permission of U.S. Pharmacist, was developed to help pharmacists counsel FM patients and their physicians about treatment options - and “to recognize patients with FMS-like symptoms who are self-treating” and may need medical treatment.

It begins with detailed statistics on symptom prevalence in FM patients, and moves through pathophysiology, typical clinical presentation, and key findings of recent medication therapy research.

Fibromyalgia Syndrome: An Update for Pharmacists
By Darrell Hulisz, RPh, PharmD & John Komara, PharmD candidate* Reproduced with permission from the January 2006 issue of U.S. Pharmacist

Fibromyalgia syndrome (FMS) is a chronic, soft-tissue pain disorder that affects about 3.7 million people in United States, the majority (75%) of whom are women.¹ The condition is characterized by fatigue and widespread pain in muscles, ligaments, and tendons and is a common cause of chronic musculoskeletal pain. Patients with FMS often report tender point pain that occurs in local sites - usually in the neck and shoulders - and radiates out into other regions of the body. Such pain can occur in areas where the muscles attach to bone or ligaments, but the joints are not affected. Pain resulting from FMS is similar to that of arthritis and has been described as stiffness, burning, radiating, and aching.

The generalized pain of FMS is often accompanied by many other symptoms, including depression, headache, paresthesias, fatigue, poor sleep, and morning stiffness (Table 1). Table 1: Symptoms Associated With FMS

As more attention is given to the pharmacological treatment of this disorder, pharmacists will likely receive questions from patients with FMS. This article will help pharmacists to effectively counsel patients with Fibromyalgia and recognize patients with FMS-like symptoms who are self-treating, since some of these patients may need medical treatment.

Epidemiology
The exact etiology and pathogenesis of FMS is essentially unknown. Due to its similarity to other disease states and lack of objective symptoms, the disorder is often difficult to diagnose. FMS affects about 2% to 3% of the general population and more than 5% of patients in general medical practice.^1,2 The typical age of patients with FMS ranges from mid-30s to late-50s. One study found that generalized musculoskeletal pain in women was increasingly prevalent as age increased from 18 to 70 years.³ Patients often report that their pain is continuous and can vary depending on time of day, weather changes, physical activity, and the presence of stressful situations. Insomnia often exacerbates the pain.

Pathophysiology
Multiple physiologic alterations such as sleep disturbances, altered neurotransmitter metabolism, and muscle structure abnormalities have been proposed to account for the symptoms associated with FMS. Such theories involving sleep and neurotransmitter alterations are widely accepted.

Poor sleeping patterns are very prevalent in patients with FMS and can affect their stress response system. This contributes to negative mood, cognitive difficulties, and increased pain perception.^4-6 The stress response may become maladaptive in chronic pain syndromes and contribute to symptoms such as fatigue, poor sleep, low mood and/or anxiety, and "flu-like" illness. ⁴

Evidence suggests that psychological stress can initiate alterations of the stress response system, with multiple adverse effects on the neuroendocrine, immunologic, and autonomic nervous systems.^5,6 Decreases in serum serotonin, which modulates pain and stage 4 sleep, have also been noted. In addition, levels of serotonin's precursor, tryptophan, may be low in patients with FMS.⁵ The theory that altered serotonin may be involved in the pathogenesis of FMS has led to the use of selective serotonin reuptake inhibitors (SSRIs) for treatment.

Other biochemical abnormalities include an elevated level of substance P in cerebral spinal fluid (80% of patients).
Hyaluronic acid levels are high early in the day, and changes in serum levels are related to the intensity of morning stiffness.⁷

The simultaneous processing of sensory and emotional aspects of pain may influence the subjective intensity of FMS symptoms. Patients with FMS have distorted central nociceptive processing, which alters the pain perception and pain tolerance thresholds. The two principal effectors of the stress response, the hypothalamic pituitary axis and the sympathetic nervous system, are activated in pain states.⁶ Negative emotions and psychological factors can heighten the pain experience and pain-processing systems.

The four principal categories of pain are:
1. Nociceptive pain (matches the noxious stimulus)
2. Neuropathic pain (may follow injuries/diseases that directly affect the nervous system)
3. Psychogenic pain (occurs in disorders associated with psychological factors), and
4. Complex pain of complex etiology (occurs in Fibromyalgia). The number of painful tender points is strongly correlated with psychological distress in patients with FMS (Table 2 at end of article).

Aggravating Factors in FMS
Fibromyalgia is a chronic illness whose outcomes are influenced by the interaction of biological, psychological, and sociological factors.8 Important biological factors include gender, sleep, physical condition, neuroendocrine and autonomic dysregulation, and sensitization to pain.

Female gender is associated with increased pain sensitivity. Clinical studies have shown that females have more pain, use analgesics more often, and are influenced by fluctuations in hormone levels.⁹ Stress and noxious stimuli are more likely to trigger a response in females than in males. Compared with men, women report more symptoms, including unexplained symptoms.^9,10

Other variables such as environment and ethnicity can influence the course of pain and fatigue. Cognitive factors in the pain and fatigue associated with FMS include hypervigilance, management strategies, perceived pain control, mood, depression, anxiety, and personal behaviors.

Psychosocial factors such as poor health of parents, poor family environment, and childhood abuse - particularly sexual abuse - may influence a patient's vulnerability or susceptibility to FMS. The disorder often has a high impact on the patient, the patient's family, and society. Physical functioning, emotional well-being, social functioning, and general health perception all contribute to the patient's quality of life. In approximately one half of cases, symptoms of FMS appeared to begin after a specific event, most often some form of physical or emotional trauma.¹¹

Typical Clinical Presentation of FMS
The chief complaint of patients with FMS is diffuse musculoskeletal pain. Several characteristics and painful "trigger points" are associated with FMS (Tables 1, 2). Although initially the pain may be localized, it can spread to many muscle groups.

Patients typically complain of pain in the neck, back, chest wall, arms, and legs. The pain is recurring and fluctuates in intensity. Sensations of tingling and burning are often described. Patients with FMS may have a variety of symptoms that are not well understood, including abdominal pain suggestive of irritable bowel syndrome and bladder symptoms indicative of interstitial cystitis.

Fatigue is one of the most common complaints. Most patients report light sleep and/or feeling groggy in the morning. Mood disturbances, short-term memory loss, headaches, and feeling faint and/or dizzy are also frequent complaints.

Less common symptoms include ocular dryness, dysphagia, palpitations, dyspnea, dysmenorrhea, osteoporosis, weight fluctuations, allergic symptoms, and night sweats.

Typically, the only helpful finding on physical exam is excessive tenderness. The rest of the exam is usually only helpful to rule out other conditions. Patients often have difficulty distinguishing joint and muscle pain and may complain of swelling, although the joints do not appear inflamed on exam. There is no evidence to indicate a connective tissue disorder unless the patient has an associated illness. FMS may occur with any rheumatic disorder.¹²

FMS frequently exists with other illness. In one study, 22% of patients with systemic lupus erythematosus met the American College of Rheumatology criteria for fibromyalgia.¹⁰ Coexisting connective tissue diseases, psychiatric illnesses, sleep disorders, and chronic infections complicate the assessment and diagnosis of FMS because of the similarities in symptoms.

Approximately 30% of patients with FMS have major mood disorders.¹³ A change in affect is often the patient's primary complaint.¹⁴ The combination of poor sleep, fatigue, and widespread pain is observed in disorders such as restless legs syndrome and sleep apnea. Pain and tenderness are also present in some patients who have an infectious disease. FMS overlaps with other poorly understood syndromes. Patients with Chronic Fatigue Syndrome often meet tender point criteria for FMS. Myofascial pain can also complicate assessment and diagnosis. Patients with Chronic Fatigue Syndrome often complain of localized pain, and some consider it to be a localized form of FMS.¹⁵

Overview of Treatment of FMS
The classification and diagnosis of FMS is a critical step in improving a patient's quality of life. The goal of FMS therapy is palliation of symptoms, since there is no curative treatment of FMS and remission of all symptoms is rarely achieved. Since there is no consensus on effective pharmacological treatment for FMS, most patients are treated symptomatically for pain, insomnia, underlying depression, and muscle tension.

Treatment is multifaceted and includes patient education, pharmacotherapy, physical and occupational therapy, and occasionally behavioral or psychotherapy. A treatment program that incorporates physicians, rehabilitation, and mental health specialists will likely be more successful than drug treatment alone.¹⁶ Results of educational interventions alone are often superior to those in control groups, with respect to pain relief.¹⁶

Educational interventions should explain the nature of FMS and provide a rationale for the treatment program. A list of resources for patients with FMS can be found in Table 3 [at end of article]. Patients should have an active role in the treatment plan, understand the role of stress, and learn techniques that can reduce it.

Pharmacotherapy
SSRIs and tricyclic antidepressants have proven to be somewhat effective. In one study, fluoxetine was superior to placebo at reducing pain and change in mood.¹⁷ Doses of up to 80 mg of fluoxetine per day were used in 60 women (ages 21 to 71 years) with FMS. Patients were randomly assigned to receive fluoxetine (10 to 80 mg/day) or placebo for 12 weeks in a double-blind, parallel-group, flexible-dose study. Women who received fluoxetine (mean dose, 45 mg/day) had a significant (P = .005) improvement of the Fibromyalgia Impact Questionnaire (FIQ) total score, compared with women who received placebo. The FIQ is a self-reported survey of 19 items that measure physical functioning and intensity of symptoms.

The fluoxetine group also showed significant improvement of their pain (P = .002), fatigue (P = .05) and depression (P = .01) scores, compared with women who received placebo. The number of tender points and total myalgic scores improved more in the fluoxetine group than in the placebo group, but these differences were not statistically significant. Fluoxetine was generally well tolerated.

A meta-analysis of clinical trials using antidepressants for the treatment of FMS shows that these drugs have only modest efficacy in treating many of the symptoms of fibromyalgia. ¹⁸ Sixteen randomized placebo-controlled trials were identified, of which 13 were appropriate for data extraction. There were three classes of antidepressants evaluated: tricyclics (nine trials), SSRIs (three trials), and S-adenosylmethionine (two trials). Patients were more than four times as likely to report overall improvement and reported moderate reductions in individual symptoms, particularly pain. It is uncertain whether this effect is independent of depression. Doses lower than those required for depression should be used at bedtime (e.g., nortriptyline 25 to 50 mg at bedtime). However, the adverse side effects of some of these drugs may limit their use, especially the highly anticholinergic drug amitriptyline.

A number of medications, including analgesic, anti-inflammatory, and central nervous system (CNS) drugs have been used in the treatment of FMS.

In 2003, a study assessed the efficacy of acetaminophen and tramadol in patients with fibromyalgia.¹⁹ The purpose of the study was to evaluate the efficacy and safety of a combination analgesic tablet (37.5 mg tramadol/325 mg acetaminophen) for the treatment of fibromyalgia pain. The 91-day, multicenter, double-blind, randomized, placebo-controlled study compared tramadol/acetaminophen combination tablets with placebo. The primary outcome variable was cumulative time to discontinuation (Kaplan-Meier analysis). Secondary measures at the end of the study included pain, pain relief, total tender points, myalgia, health status, and FIQ scores. There were 315 subjects enrolled in the study, 94% female.

Tramadol/acetaminophen–treated subjects had significantly less pain at the end of the study, better pain relief, and better FIQ scores (all statistically significant). Indexes of physical functioning, role-physical, body pain, health transition, and physical component summary improved significantly in subjects receiving the tramadol/acetaminophen tablets. Discontinuation due to adverse events occurred in 19% (n = 29) of tramadol/acetaminophen-treated subjects and 12% (n = 18) of placebo-treated subjects. Patients who had experienced treatment failure on other medications were excluded. In addition, tramadol as a weak mu-receptor agonist has some abuse potential and should be prescribed with caution.

In a study of 58 females with fibromyalgia, 74.1% completed an eight-week treatment period testing the combination of carisoprodol, acetaminophen, and caffeine versus placebo.²⁰ Twenty-three patients received placebo and 20 received active medication. In the placebo group, 56.5% of patients used additional analgesics, compared to only 20% in the active treatment group (P = .015). Forty-three percent of patients in the placebo group and none of the patients in the active treatment group used tricyclic antidepressants, anxiolytics, or sedatives (P = .0008).

Patients receiving active medication reported statistically significant improvement for pain (P <.01), sleep quality (P <.01) and a general feeling of sickness (P <.05). An increased pressure pain threshold was found in the active treatment group after eight weeks in 70% of the sites measured, while the pressure pain threshold increased in only 30% of the sites in the placebo group. The authors concluded that the combination of carisoprodol, acetaminophen, and caffeine is effective in the treatment of fibromyalgia. However, the study's small sample size should be considered.

A randomized crossover trial studied the use of fluoxetine and amitriptyline together.²¹ This combination provided better results than either drug alone. The use of a drug or combination of drugs that inhibit reuptake of both serotonin and norepinephrine may be more useful than a drug that targets only one neurotransmitter.

Duloxetine and venlafaxine are two drugs that inhibit reuptake of both neurotransmitters and may be useful in the treatment of FMS.

Pregabalin is an alpha-2 delta ligand being studied for chronic pain and epilepsy. A recent trial was conducted to evaluate the efficacy and safety of pregabalin for treatment of symptoms associated with FMS.²² The multicenter, double-blind, eight-week, randomized study measured the effect of pregabalin doses of 150, 300, and 450 mg/day on pain, sleep, fatigue, and health-related quality of life in patients with FMS (n = 529) against placebo. The primary outcome was the comparison of mean end-point pain scores, derived from daily diary ratings of pain intensity from the pregabalin treatment groups and the placebo group.

Pregabalin at 450 mg/day significantly reduced the average severity of pain in the primary analysis compared with placebo. Significantly more patients treated with pregabalin had improvement in pain at the end point (29% vs. 13% in the placebo group; P = .003). Pregabalin at 300 and 450 mg/day was associated with significant improvements in sleep quality, fatigue, and global measures of change. Dizziness and somnolence were the most frequently reported adverse effects. Rates of discontinuation due to adverse events were similar across all treatment and placebo groups. The authors concluded that pregabalin at 450 mg/day was well tolerated and effective to treat FMS compared with placebo, resulting in reduced symptoms of pain, disturbed sleep, and fatigue.

Duloxetine was studied in 207 patients with primary fibromyalgia, with or without current major depressive disorder.²³ The study was a randomized, double-blind, placebo-controlled trial conducted in 18 outpatient research centers in the U.S. Subject charcteristics were as follows: 89% female, 87% white, mean age of 49 years, and 38% with a current major depressive disorder. After a single-blind placebo treatment for one week, subjects were randomly assigned to receive duloxetine 60 mg twice a day or placebo for 12 weeks.

Compared with placebo, duloxetine-treated subjects showed significantly greater improvement of pain, fibromyalgia, and quality of life. Duloxetine treatment improved fibromyalgia symptoms and severity of pain regardless of baseline status of depression. Compared with placebo-treated females, duloxetine-treated females showed greater improvement on most efficacy measures, while duloxetine-treated male subjects failed to improve significantly. However, it is important to note that there were far fewer male subjects in the study. In females, the effect of treatment on pain reduction was independent of the effect on mood or anxiety. Duloxetine was well tolerated, with adverse effects being similar to those reported with placebo.

Cyclobenzaprine has been shown to be mildly effective in a meta-analysis of placebo-controlled trials.²⁴ The meta-analysis showed that when patients are treated with cyclobenzaprine, they are three times as likely to report an improvement in pain. Five patients would need to be treated with the drug in order for one to improve. According to this analysis, generalized pain improved early on with the drug, but there was no improvement in fatigue or tender points at any time.

Using a variety of outcome measures, cyclobenzaprine-treated patients were three times as likely to report overall improvement and moderate reductions in individual symptoms, particularly sleep. A 5- to 10-mg dose three times daily was used. Patients should be warned of prominent CNS [central nervous system] side effects with cyclobenzaprine, including dizziness, sedation, and dry mouth.

Nonmedicinal Options
There are a number of nonmedicinal options that may be effective for the treatment of fibromyalgia. FMS patients typically avoid exercise because they believe that their pain worsens after exercise. Aerobic activities such as biking, swimming, and running are sometimes successful in attenuating FMS symptoms. In controlled trials, aerobic exercise was able to decrease the amount of pain reported and increased the threshold for pain.^25,26 Strength training using weights and elastic bands has been effective in reducing pain and the number of tender points.²⁶

Complementary and alternative medicine (CAM) is sometimes used by FMS patients. However, evidence to confirm its effectiveness is limited. It is important that the physician and pharmacist be aware of all CAM substances the patient is taking, since some may have drug interactions with prescribed therapy.

Some studies have shown that S -adenosylmethionine can reduce pain and improve quality of sleep and sense of well-being, while other studies have shown no benefit.^27,28 In addition, 5-hydroxytryptophan (5-HTP), the precursor to serotonin, has been shown to have some benefit in FMS patients.²⁹ Oral doses of 5-HTP 100 mg three times daily improved pain severity, quality of sleep, anxiety, and the number of tender points.

Additional options include hypnotherapy, meditation, and cognitive behavioral therapy.^30,31 These options have shown some usefulness in selected FMS patients.

Pharmacist-to-Patient Counseling
Pharmacists should reassure patients with FMS that improvement in pain tolerance, sleep, and fatigue is likely with appropriate comprehensive and multidisciplinary treatment. However, patients should understand that there is no cure for FMS, and complete pain relief is often not possible. Pharmacists should emphasize that active patient participation in the treatment program can help reduce symptoms and improve quality of life. Patients should be educated about the possible causes and aggravating factors of FMS.

Table 2: Location of Trigger Points
n Suboccipital muscle insertions at occiput
n Lover cervical paraspinals
n Trapezius at midpoint of the upper border
n Supraspinatus at its origin above medial scapular spine
n Second Costochondral junction
n 2 cm distal to lateral epicondyle in forearm
n Upper outer quadrant of buttock
n Greater trochanter
n Knee, just proximal to the medial joint line
Source: Reference 3

Table 3: Resources for Patients with Fibromyalgia
The Arthritis Foundation www.arthirtis.org
National Chronic Fatigue Syndrome & Fibromyalgia Assoc. www.ncfsfa.org
The Fibromyalgia Partnership www.fmpartnership.org
Fibromyalgia Network www.fmenetnews.com American Fibromyalgia Syndrome Association, www.afsafund.org

______
* About the authors. Darrell Hulisz, RPh, PharmD, is Associate Professor of Family Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio; and Associate Clinical Professor of Pharmacy Practice, Ohio Northern University College of Pharmacy, Ada, Ohio. John Komara is a PharmD candidate at Ohio Northern University and Pharmacy Intern, Family Medicine Foundation, Cleveland, Ohio.

References
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4. Goldenberg DL. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol. 1994;6:223-233.
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13. Hudson JI, Goldenberg DL, Pope HG, et al. Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med. 1992;92:363-367.
14. Giesecke T, Williams DA, Harris RE, et al. Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum . 2003;48:2916-2922.
15. Wolfe F, Simons DG, Fricton J, et al. The fibromyalgia and myofascial pain syndromes: A preliminary study of tender points and trigger points in persons with fibromyalgia, myofascial pain syndrome and no disease. J Rheumatol. 1992;19:944-951.
16. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA . 2004;292:2388-2395.
17. Arnold LM, Hess EV, Hudson JI, et al. A randomized, placebo-controlled, double-blind, flexible-dose study fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112:191-197.
18. O'Malley PG, Balden E, Tomkins G, et al. Treatment of fibromyalgia with antidepressants: a meta-analysis. J Gen Intern Med. 2000;15:659-666.
19. Bennett RM, Kamin M, Karim R, Rosenthal N. 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.
20. Vaeroy H, Abrahamsen A, Forre O, Kass E. Treatment of fibromyalgia: a parallel double blind trial with carisoprodol, paracetamol, and caffeine versus placebo. Clin Rheumatol. 1989;8:245-250.
21. Goldenberg DL, Mayskiy M, Mossey CJ, et al. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852-1859.
22. Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:1264-1273.
23. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004;50:2974-2984.
24. Tofferi JK, Jackson JL, O'Malley PG. Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis Rheum. 2004;51:9-13.
25. Busch A, Schachter CL, Peloso PM, Bombardier C. Exercise for treating fibromyalgia syndrome. Cochrane Database Syst Rev. 2002;CD003786.
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28. Volkmann H, Norregaard J, Jacobsen S, et al. Double-blind, placebo-controlled crossover study of intravenous S-adenosyl-L-methionine in patients with fibromyalgia. Scand J Rheumatol. 1997;26:206-211.
29. Puttini PS, Caruso I. Primary fibromyalgia syndrome and 5-hydroxy-L-tryptophan: a 90-day open study. J Int Med Res. 1992;20:182-189.
30. Haanen HCM, Hoenderdos HTW, Van Romunde LKJ, et al. Controlled trial of hypnotherapy in the treatment of refractory fibromyalgia. J Rheumatol. 1991;18:72-75.
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Note: This information is not meant to diagnose, treat, or cure any disease. It is essential for patients to discuss and review any potential changes in their health support plans collaboratively with their professional healthcare team.