David Baxter PhD
Late Founder
Fibromyalgia: New Insights Into a Misunderstood Condition
by Jack J. Chen, PharmD, BCPS, CGP, FCPhA
American Pharmacists Association 2008 Annual Meeting
June 9, 2008
Despite the classification of fibromyalgia nearly 20 years ago, this chronic condition continues to be shrouded in controversy and skepticism. At the recent annual meeting of the American Pharmacists Association (APhA), experts provided an evidence-based discussion of the fibromyalgia syndrome. The information provided there was intended to help clinicians better understand current diagnostic and therapeutic considerations of this medical disorder.
Ironically, the lead author on the 1990 diagnostic guidelines was originally a skeptic who questioned the credibility of fibromyalgia, said Linda Krypel, PharmD, Professor of Pharmacy Practice at Drake University College of Pharmacy and Health Sciences, Des Moines, Iowa. The recent publication of treatment guidelines and the emergence of a new therapy for fibromyalgia can be viewed as trends toward increased acceptance of this condition by the medical community.
Fibromyalgia is the most common chronic pain syndrome encountered in general medicine and rheumatology. Approximately 2% to 10% of the US population (more than 6 million people) are believed to meet the current diagnostic criteria for fibromyalgia. The disorder overwhelmingly affects more females than males.
Fibromyalgia is characterized by multiple symptoms, of which chronic, widespread pain is the sine qua non. Classification criteria established by the American College of Rheumatology (ACR) include diffuse soft-tissue pain that is present for at least 3 months, and pain on palpation in at least 11 of 18 tender points. Table 1 (see attachment) outlines the symptoms of fibromyalgia and common situations or triggers that can aggravate the condition.
If a patient reports chronic widespread pain, clinicians should look for other symptoms of fibromyalgia such as non-refreshing sleep, fatigue, presence of tender or trigger points (commonly found on the elbows, inside of the knees, on or near the neck, and laterally on both hips), and cognitive problems (such as memory loss, language and learning difficulties), often referred to as "fibrofog." If fibromyalgia syndrome is suspected, the patient should be referred to a clinician familiar with treating the condition.
Neurotransmitter Dysfunction and Sensitized Nociceptive Pathways
The pathophysiology of fibromyalgia is complex and multifactorial, Dr. Kryper explained. Currently, fibromyalgia is considered a disorder of pain regulation, due in part to heightened generalized pain sensitivity that arises from pathologic processing of nociceptive stimuli. Central and peripheral sensitization of nociceptive systems and hypothalamic-pituitary-adrenal axis dysfunction are involved.
Reduced levels of bioaminergic neurotransmitters, such as dopamine, norepinephrine, and serotonin, are believed to play a major role in pathologic nociceptive sensitization. Defects in serotonin transporters and decreased dopamine and norepinephrine levels have been documented and associated with decreased delta sleep and higher than normal activity of substance P.
Additionally, sensitization of peripheral nociceptive pathways is associated with chronic sympathetic activation, resulting in muscle hypoxia and exercise intolerance. Table 2 (see attachment) provides a more extensive overview of the pathophysiologic mechanisms involved in
fibromyalgia.
The Role of Nonpharmacologic Management
Evidence-based treatment guidelines for fibromyalgia have become available only recently. Raylene M. Respond, PharmD, Dean and Professor of Pharmacy Practice, Drake University, summarized the Guidelines for the Management of Fibromyalgia Syndrome Pain in Adults and Children from the American Pain Society (APS), and the European League Against Rheumatism (EULAR) recommendations for management of fibromyalgia syndrome.
Of the 2, the EULAR guidelines are more recent, and they use more restrictive criteria to analyze currently available evidence, Dr. Respond said. For instance, clinical studies must have measured pain by visual analog scale and have measured function by the Fibromyalgia Impact Questionnaire (FIQ). These guidelines also recommend agents not currently available in the United States.
Treatment recommendations in both guidelines are based upon the type of evidence available, ranging from strong (eg, consistent benefit as supported by randomized, controlled trials) to weak (eg, supported only by nonrandomized trial data) (Table 3 - see attachment). A key point of both the APS and EULAR treatment guidelines is that various nonpharmacologic and pharmacologic interventions are supported by strong levels of evidence, and the combination of both forms of therapy is encouraged.
Nonpharmacologic treatments are an important component of fibromyalgia management and should not be overlooked. Clinicians should educate patients that integrating exercise or increased physical activity into their daily routine is important and beneficial in managing fibromyalgia. The goals of increased physical activity and exercise are to improve or maintain general fitness and overall health, give the patient a feeling of control over the condition, and improve physical function and emotional well-being, which often are negatively affected by fibromyalgia.
The clinician-patient relationship provides a unique opportunity to use targeted discussions, support, and consistent follow-up to encourage fibromyalgia patients to adopt a more physically active lifestyle. Examples of beneficial exercise include strength training, aerobic conditioning, aquatic therapy, and stretches and balance exercises. Patients should start slowly with a few minutes of exercise per day and increase gradually up to 30 minutes per day. Routine exercise also reduces stress, which can exacerbate fibromyalgia symptoms.
Patients should be encouraged to seek information about fibromyalgia through organized programs and educational resources (eg, National Fibromyalgia Association, American College of Rheumatology). Finally, complementary and alternative techniques (eg, acupuncture, biofeedback) may be considered if exercise, stress reduction, and education combined with pharmacologic treatment are not achieving desired results.
Restoring Neurotransmitter Balance Through Pharmacology
According to Dr. Rospond, strong evidence has emerged to support the use of various pharmacologic agents for managing fibromyalgia symptoms (Table 4 - see attachment). These agents include cyclobenzaprine, duloxetine, gabapentin, pregabalin, tramadol, and the tricyclic antidepressants. Pregabalin is currently the only drug approved by the US Food and Drug Administration (FDA) for management of fibromyalgia.
Tricyclic Agents
Tricyclic agents (antidepressants and cyclobenzaprine) represent an older class of drugs that is still considered the first line of therapy for fibromyalgia. These agents have been clinically evaluated more than any other class of drugs. The primary agents in this class are amitriptyline (a tricyclic antidepressant) and cyclobenzaprine (a tricyclic muscle relaxant).
Amitriptyline inhibits presynaptic reuptake of serotonin (and norepinephrine to a small degree). Increases in synaptic serotonin and norepinephrine are associated with increased slow wave sleep or delta sleep, as well as increased release of endogenous endorphins. Because anticholinergic adverse effects are common with amitriptyline (and other tricyclic antidepressants), the dosage should be increased slowly to obtain maximum efficacy with minimal side effects.
Amitriptyline should be initiated at low doses (eg, 5-10 mg taken 1-3 hours before bedtime and increased by 5 mg every 2 weeks until a target maintenance dose of 25-50 mg is achieved). Daily doses at this level produce clinical improvements in pain, sleep, fatigue, and overall wellbeing in 25% to 45% of patients with fibromyalgia.
Cyclobenzaprine, commonly used as a muscle relaxant in the United States, is structurally related to the tricyclic antidepressants. This drug has been shown to modify the descending nociceptive pathways by decreasing gamma and alpha efferent neuron activity originating at the brain stem. The dosage should be started at 5-10 mg taken at bedtime and increased to 20-30 mg, taken either at night or in divided doses during the day. Compared with amitriptyline, cyclobenzaprine may be associated with better patient acceptance due to fewer side effects and more rapid onset of relief.
Serotonin-Norepinephrine Reuptake Inhibitors and Selective Serotonin Reuptake Inhibitors
Currently available evidence suggests that certain serotonin-norepinephrine reuptake inhibitors (SNRIs) are effective for fibromyalgia, although more studies of specific agents within this class are needed. In April 2007, the manufacturer of duloxetine filed a new drug application for a fibromyalgia indication. Duloxetine is a reuptake inhibitor of serotonin and norepinephrine, and to a lesser extent, dopamine.
Analysis of pooled data from two 12-week randomized, placebo-controlled, double-blind clinical trials found that duloxetine 60 mg daily or 60 mg twice daily in women with fibromyalgia was superior to placebo on all efficacy measures, including pain scores, mean tender point threshold, Clinical Global Impression of Severity, and Patient Global Impression of Improvement. The results of this pooled analysis suggest that duloxetine is an effective treatment for both the pain and functional impairment associated with fibromyalgia in female patients.
However, another randomized, double-blind, placebo-controlled study did not find any difference between placebo, duloxetine 60 mg once daily, or duloxetine 120 mg once daily on the primary outcomes of pain severity and self-reported global improvement scores at the end of a 6-month treatment period.[28] While between-group differences on the primary outcomes were noted at several timepoints throughout the study, differences at 6 months were non-significant. Duloxetine-treated patients did maintain significant improvement compared with placebo on secondary measures such as mental health, clinician-rated global improvement, and fatigue scores.
This latter study was 1 of only a few long-term (ie, 6 months or longer) studies, Dr. Rospond noted, and the results raise questions about the long-term efficacy of duloxetine as well as other agents studied, because the duration of most blinded studies of fibromyalgia treatment is only up to 12 weeks long.
For the treatment of fibromyalgia, doses of duloxetine are initiated at 20 mg daily and titrated to 60 mg twice daily over a 2-week period. Titration minimizes the incidence of side effects, such as constipation, dry mouth, nausea, and sleepiness. Clinicians should also be aware that a recent FDA statement prohibits the use of duloxetine in patients with any type of hepatic insufficiency.
Some clinicians have also been treating fibromyalgia with venlafaxine, which selectively inhibits neuronal uptake of serotonin, norepinephrine, and dopamine. However, studies using 75 mg per day for 6 weeks have yielded variable results, and additional studies are warranted.
Milnacipran (not marketed in the United States) belongs to the same class of drugs as duloxetine but exhibits greater inhibition of norepinephrine reuptake. In December 2007, the manufacturers of milnacipran filed a new drug application for a fibromyalgia indication. Milnacipran doses of 100 mg once or twice daily have demonstrated significant improvement in the outcomes of pain, mood, global wellbeing, function, and fatigue. Adverse effects include anxiety, dysuria, itchiness, nausea, sweating, shivering, and vertigo.
Agents with the most selectivity and specificity for serotonin reuptake inhibition appear to be associated with lower efficacy in fibromyalgia, Dr. Rospond said. For example, citalopram, a selective serotonin-reuptake inhibitor (SSRI) with high selectivity, has shown no efficacy (in terms of the primary outcome of pain severity) in studies of patients with fibromyalgia, while fluoxetine (a lower selectivity SSRI compared with citalopram) has been found effective for fibromyalgia. However, citalopram has demonstrated improvement on secondary outcomes such as sleep, cognitive function, fatigue, and concomitant depression.
Pregabalin: First FDA-Approved Agent for Fibromyalgia
In June 2007, pregabalin became the first agent to receive FDA-approved labeling for the treatment of fibromyalgia. (Pregabalin also carries FDA-approved indications for management of partial seizures, painful diabetic peripheral neuropathy, and postherpetic neuralgia.) Unlike other agents that work by modulating serotonin and norepinephrine activity, researchers believe that pregabalin works by inhibiting excitatory inputs to the spinal cord and raising the threshold required to activate nociceptive neurons. Pregabalin also increases delta sleep.
In fibromyalgia studies, pregabalin improved outcomes of pain, fatigue, sleep, and quality of life. In an 8-week placebo-controlled study, patients with fibromyalgia were randomized to treatment with placebo or 1 of 3 pregabalin doses (150 mg, 300 mg, or 450 mg once daily). At the end of the study, the 450 mg dose was associated with a significantly greater reduction in pain severity and fatigue than placebo. In addition, a 50% reduction in pain was reported by about 30% of subjects in the 450 mg dose group compared with fewer than 15% of subjects in the placebo group. Patients treated with 150 mg and 300 mg also demonstrated significant improvement. The 2 higher doses of pregabalin were also associated with significant improvements in sleep quality.
In a second double-blind, placebo-controlled trial, monotherapy with pregabalin was found to be efficacious and safe for treatment of pain associated with fibromyalgia. Subjects were randomized to placebo or pregabalin 300 mg, 450 mg, or 600 mg per day (doses divided and taken twice daily) for 13 weeks. Patients in all of the pregabalin-treated groups showed significant improvement in pain compared with placebo, as well as improvements in assessments of sleep and patients' impressions of their global improvement.
Therapy with pregabalin should be initiated at 75 mg twice daily and increased to 150 mg twice daily over 7 days. Dr. Rospond pointed out that effects can be seen quickly (within 1 week), and recent data demonstrate sustained effectiveness for 6 months or longer. Adverse effects include blurred vision, constipation, dizziness, drowsiness, edema, and weight gain.
Although not FDA-indicated for fibromyalgia, gabapentin has also demonstrated efficacy for fibromyalgia at doses of 1200 mg to 2400 mg per day in 3 divided doses. The most frequent side effects of gabapentin include sedation and dizziness. The incidence of edema with gabapentin appears to be lower than that with pregabalin.
Analgesics
With diffuse pain being the primary symptom of fibromyalgia, it would seem logical to include analgesics in the treatment plan. Tramadol, an atypical opioid, is the only analgesic with demonstrated efficacy in treating fibromyalgia. Not only does tramadol bind to the mu-opiate receptors in the central nervous system, it also inhibits the reuptake of serotonin and norepinephrine. These latter effects on neurotransmitter activity may partially explain tramadol's effectiveness in treating fibromyalgia.
In a randomized, double-blind, placebo-controlled clinical trial, patients with fibromyalgia were first enrolled into an open-label phase and treated with tramadol 50-400 mg per day. Patients who tolerated a perceived benefit from tramadol were then randomized to continued treatment with tramadol or placebo in a 6-week double-blinded phase. The primary efficacy outcome measure was time to exit from the double-blind phase because of inadequate pain relief. Significantly more subjects in the tramadol group completed the double-blind phase compared with those in the placebo group.
Tramadol in combination with acetaminophen is also effective for fibromyalgia. In a 3-month, randomized, double-blind study, tramadol with acetaminophen (37.5 mg tramadol with 325 mg acetaminophen) administered 4 times daily was compared with placebo. At the end of the study, tramadol-treated patients recorded significantly less pain, better pain relief, and greater improvement in FIQ scores than placebo-treated patients.
To minimize dizziness and vertigo, tramadol therapy should be initiated at a dose of 25 mg per day and titrated every 3 days in 25 mg increments until a total dose of 100 mg (25 mg 4 times daily) is achieved. Doses may then be increased incrementally every 3 days to a total of 200 mg (50 mg 4 times daily). Caution must be employed to avoid prescribing more than 4 g of acetaminophen per day to reduce the risk of hepatotoxicity with chronic therapy.
Dr. Rospond reminded the audience that the evidence supporting the effectiveness of nonsteroidal anti-inflammatory agents for fibromyalgia is weak. Additionally, data are insufficient to support the use of narcotic opioids or corticosteroids to reduce fibromyalgia pain. These agents should only be considered when patients are experiencing inadequate benefit or intolerable side effects from other agents.
Miscellaneous Agents
Benzodiazepines and nonbenzodiazepine hypnotics have not demonstrated efficacy in reducing pain or improving function in fibromyalgia. However, drugs within these classes (eg, zolpidem) can be useful as add-on therapies for persistent insomnia.
Preliminary data suggest that pramipexole, a dopamine receptor agonist approved in the United States for the treatment of Parkinson's disease and restless legs syndrome, is also effective for fibromyalgia. In 1 randomized, double-blind, placebo-controlled, 14-week trial, pramipexole 4.5 mg every evening improved outcomes for pain, fatigue, and overall function. Postmarketing reports of pathologic compulsive behaviors (eg, pathologic gambling) have been reported in patients with Parkinson's disease and restless leg syndrome who were taking dopamine agonists. Whether this would occur in patients with fibromyalgia is unknown and deserves further exploration.
Tropisetron is an antiemetic that blocks the serotonin 5-HT3 receptor and increases levels of serotonin. Although not available in the United States, preliminary data suggest efficacy in treating fibromyalgia.
Although a variety of other agents hold promise for fibromyalgia therapy, several have no evidence or only weak evidence to support their use. (Table 4 - see attachment) Recombinant human growth hormone has been tested in women with fibromyalgia and low serum insulin-like growth factor (IGF) levels. In 1 trial, doses of 0.0125 mg/kg were administered subcutaneously once daily (to maintain an IGF-1 level of about 250 ng/mL) for 9 months. At the end of that period, the treated group experienced significant improvement in symptoms (as measured by the FIQ) and signs (measured by the tender point score). Although patients experienced an improvement in functional ability, complete remission of symptoms was not observed. In general there was a lag of about 6 months before patients started to note improvement.
Sodium oxybate is a commercially available preparation of naturally occurring gamma hydroxybutyrate. Doses of 6 g at bedtime have resulted in significant improvements in pain, tenderness, sleep quality, and fatigue. Other agents with no evidence or only weak evidence of efficacy in the management of fibromyalgia include calcitonin, , dehydroepiandrosterone , guaifenesin, 5-hydroxytryptamine, magnesium, melatonin, S-adenosyl-methionine , and thyroid hormones. Further study is needed with all of these agents.
Conclusion
Although fibromyalgia remains a challenging condition to manage, a number of effective therapies are available for patients (Table 5 - see attachment). Only 1 agent, pregabalin, is FDA-approved for the treatment of fibromyalgia, but clinicians should be familiar with other agents that are also effective, as supported by available scientific evidence.
Clinicians can serve as important resources for patients with fibromyalgia. They can help educate patients on the scientific mechanisms of fibromyalgia (ie, involvement of neurotransmitter and nociceptive pathways), the role of nonpharmacologic modalities, and the benefits and risks of available pharmacotherapies. Pharmacists can also assist with selection of nonprescription products for concomitant symptoms such as constipation, headache, and sleep difficulties.
by Jack J. Chen, PharmD, BCPS, CGP, FCPhA
American Pharmacists Association 2008 Annual Meeting
June 9, 2008
Despite the classification of fibromyalgia nearly 20 years ago, this chronic condition continues to be shrouded in controversy and skepticism. At the recent annual meeting of the American Pharmacists Association (APhA), experts provided an evidence-based discussion of the fibromyalgia syndrome. The information provided there was intended to help clinicians better understand current diagnostic and therapeutic considerations of this medical disorder.
Ironically, the lead author on the 1990 diagnostic guidelines was originally a skeptic who questioned the credibility of fibromyalgia, said Linda Krypel, PharmD, Professor of Pharmacy Practice at Drake University College of Pharmacy and Health Sciences, Des Moines, Iowa. The recent publication of treatment guidelines and the emergence of a new therapy for fibromyalgia can be viewed as trends toward increased acceptance of this condition by the medical community.
Fibromyalgia is the most common chronic pain syndrome encountered in general medicine and rheumatology. Approximately 2% to 10% of the US population (more than 6 million people) are believed to meet the current diagnostic criteria for fibromyalgia. The disorder overwhelmingly affects more females than males.
Fibromyalgia is characterized by multiple symptoms, of which chronic, widespread pain is the sine qua non. Classification criteria established by the American College of Rheumatology (ACR) include diffuse soft-tissue pain that is present for at least 3 months, and pain on palpation in at least 11 of 18 tender points. Table 1 (see attachment) outlines the symptoms of fibromyalgia and common situations or triggers that can aggravate the condition.
If a patient reports chronic widespread pain, clinicians should look for other symptoms of fibromyalgia such as non-refreshing sleep, fatigue, presence of tender or trigger points (commonly found on the elbows, inside of the knees, on or near the neck, and laterally on both hips), and cognitive problems (such as memory loss, language and learning difficulties), often referred to as "fibrofog." If fibromyalgia syndrome is suspected, the patient should be referred to a clinician familiar with treating the condition.
Neurotransmitter Dysfunction and Sensitized Nociceptive Pathways
The pathophysiology of fibromyalgia is complex and multifactorial, Dr. Kryper explained. Currently, fibromyalgia is considered a disorder of pain regulation, due in part to heightened generalized pain sensitivity that arises from pathologic processing of nociceptive stimuli. Central and peripheral sensitization of nociceptive systems and hypothalamic-pituitary-adrenal axis dysfunction are involved.
Reduced levels of bioaminergic neurotransmitters, such as dopamine, norepinephrine, and serotonin, are believed to play a major role in pathologic nociceptive sensitization. Defects in serotonin transporters and decreased dopamine and norepinephrine levels have been documented and associated with decreased delta sleep and higher than normal activity of substance P.
Additionally, sensitization of peripheral nociceptive pathways is associated with chronic sympathetic activation, resulting in muscle hypoxia and exercise intolerance. Table 2 (see attachment) provides a more extensive overview of the pathophysiologic mechanisms involved in
fibromyalgia.
The Role of Nonpharmacologic Management
Evidence-based treatment guidelines for fibromyalgia have become available only recently. Raylene M. Respond, PharmD, Dean and Professor of Pharmacy Practice, Drake University, summarized the Guidelines for the Management of Fibromyalgia Syndrome Pain in Adults and Children from the American Pain Society (APS), and the European League Against Rheumatism (EULAR) recommendations for management of fibromyalgia syndrome.
Of the 2, the EULAR guidelines are more recent, and they use more restrictive criteria to analyze currently available evidence, Dr. Respond said. For instance, clinical studies must have measured pain by visual analog scale and have measured function by the Fibromyalgia Impact Questionnaire (FIQ). These guidelines also recommend agents not currently available in the United States.
Treatment recommendations in both guidelines are based upon the type of evidence available, ranging from strong (eg, consistent benefit as supported by randomized, controlled trials) to weak (eg, supported only by nonrandomized trial data) (Table 3 - see attachment). A key point of both the APS and EULAR treatment guidelines is that various nonpharmacologic and pharmacologic interventions are supported by strong levels of evidence, and the combination of both forms of therapy is encouraged.
Nonpharmacologic treatments are an important component of fibromyalgia management and should not be overlooked. Clinicians should educate patients that integrating exercise or increased physical activity into their daily routine is important and beneficial in managing fibromyalgia. The goals of increased physical activity and exercise are to improve or maintain general fitness and overall health, give the patient a feeling of control over the condition, and improve physical function and emotional well-being, which often are negatively affected by fibromyalgia.
The clinician-patient relationship provides a unique opportunity to use targeted discussions, support, and consistent follow-up to encourage fibromyalgia patients to adopt a more physically active lifestyle. Examples of beneficial exercise include strength training, aerobic conditioning, aquatic therapy, and stretches and balance exercises. Patients should start slowly with a few minutes of exercise per day and increase gradually up to 30 minutes per day. Routine exercise also reduces stress, which can exacerbate fibromyalgia symptoms.
Patients should be encouraged to seek information about fibromyalgia through organized programs and educational resources (eg, National Fibromyalgia Association, American College of Rheumatology). Finally, complementary and alternative techniques (eg, acupuncture, biofeedback) may be considered if exercise, stress reduction, and education combined with pharmacologic treatment are not achieving desired results.
Restoring Neurotransmitter Balance Through Pharmacology
According to Dr. Rospond, strong evidence has emerged to support the use of various pharmacologic agents for managing fibromyalgia symptoms (Table 4 - see attachment). These agents include cyclobenzaprine, duloxetine, gabapentin, pregabalin, tramadol, and the tricyclic antidepressants. Pregabalin is currently the only drug approved by the US Food and Drug Administration (FDA) for management of fibromyalgia.
Tricyclic Agents
Tricyclic agents (antidepressants and cyclobenzaprine) represent an older class of drugs that is still considered the first line of therapy for fibromyalgia. These agents have been clinically evaluated more than any other class of drugs. The primary agents in this class are amitriptyline (a tricyclic antidepressant) and cyclobenzaprine (a tricyclic muscle relaxant).
Amitriptyline inhibits presynaptic reuptake of serotonin (and norepinephrine to a small degree). Increases in synaptic serotonin and norepinephrine are associated with increased slow wave sleep or delta sleep, as well as increased release of endogenous endorphins. Because anticholinergic adverse effects are common with amitriptyline (and other tricyclic antidepressants), the dosage should be increased slowly to obtain maximum efficacy with minimal side effects.
Amitriptyline should be initiated at low doses (eg, 5-10 mg taken 1-3 hours before bedtime and increased by 5 mg every 2 weeks until a target maintenance dose of 25-50 mg is achieved). Daily doses at this level produce clinical improvements in pain, sleep, fatigue, and overall wellbeing in 25% to 45% of patients with fibromyalgia.
Cyclobenzaprine, commonly used as a muscle relaxant in the United States, is structurally related to the tricyclic antidepressants. This drug has been shown to modify the descending nociceptive pathways by decreasing gamma and alpha efferent neuron activity originating at the brain stem. The dosage should be started at 5-10 mg taken at bedtime and increased to 20-30 mg, taken either at night or in divided doses during the day. Compared with amitriptyline, cyclobenzaprine may be associated with better patient acceptance due to fewer side effects and more rapid onset of relief.
Serotonin-Norepinephrine Reuptake Inhibitors and Selective Serotonin Reuptake Inhibitors
Currently available evidence suggests that certain serotonin-norepinephrine reuptake inhibitors (SNRIs) are effective for fibromyalgia, although more studies of specific agents within this class are needed. In April 2007, the manufacturer of duloxetine filed a new drug application for a fibromyalgia indication. Duloxetine is a reuptake inhibitor of serotonin and norepinephrine, and to a lesser extent, dopamine.
Analysis of pooled data from two 12-week randomized, placebo-controlled, double-blind clinical trials found that duloxetine 60 mg daily or 60 mg twice daily in women with fibromyalgia was superior to placebo on all efficacy measures, including pain scores, mean tender point threshold, Clinical Global Impression of Severity, and Patient Global Impression of Improvement. The results of this pooled analysis suggest that duloxetine is an effective treatment for both the pain and functional impairment associated with fibromyalgia in female patients.
However, another randomized, double-blind, placebo-controlled study did not find any difference between placebo, duloxetine 60 mg once daily, or duloxetine 120 mg once daily on the primary outcomes of pain severity and self-reported global improvement scores at the end of a 6-month treatment period.[28] While between-group differences on the primary outcomes were noted at several timepoints throughout the study, differences at 6 months were non-significant. Duloxetine-treated patients did maintain significant improvement compared with placebo on secondary measures such as mental health, clinician-rated global improvement, and fatigue scores.
This latter study was 1 of only a few long-term (ie, 6 months or longer) studies, Dr. Rospond noted, and the results raise questions about the long-term efficacy of duloxetine as well as other agents studied, because the duration of most blinded studies of fibromyalgia treatment is only up to 12 weeks long.
For the treatment of fibromyalgia, doses of duloxetine are initiated at 20 mg daily and titrated to 60 mg twice daily over a 2-week period. Titration minimizes the incidence of side effects, such as constipation, dry mouth, nausea, and sleepiness. Clinicians should also be aware that a recent FDA statement prohibits the use of duloxetine in patients with any type of hepatic insufficiency.
Some clinicians have also been treating fibromyalgia with venlafaxine, which selectively inhibits neuronal uptake of serotonin, norepinephrine, and dopamine. However, studies using 75 mg per day for 6 weeks have yielded variable results, and additional studies are warranted.
Milnacipran (not marketed in the United States) belongs to the same class of drugs as duloxetine but exhibits greater inhibition of norepinephrine reuptake. In December 2007, the manufacturers of milnacipran filed a new drug application for a fibromyalgia indication. Milnacipran doses of 100 mg once or twice daily have demonstrated significant improvement in the outcomes of pain, mood, global wellbeing, function, and fatigue. Adverse effects include anxiety, dysuria, itchiness, nausea, sweating, shivering, and vertigo.
Agents with the most selectivity and specificity for serotonin reuptake inhibition appear to be associated with lower efficacy in fibromyalgia, Dr. Rospond said. For example, citalopram, a selective serotonin-reuptake inhibitor (SSRI) with high selectivity, has shown no efficacy (in terms of the primary outcome of pain severity) in studies of patients with fibromyalgia, while fluoxetine (a lower selectivity SSRI compared with citalopram) has been found effective for fibromyalgia. However, citalopram has demonstrated improvement on secondary outcomes such as sleep, cognitive function, fatigue, and concomitant depression.
Pregabalin: First FDA-Approved Agent for Fibromyalgia
In June 2007, pregabalin became the first agent to receive FDA-approved labeling for the treatment of fibromyalgia. (Pregabalin also carries FDA-approved indications for management of partial seizures, painful diabetic peripheral neuropathy, and postherpetic neuralgia.) Unlike other agents that work by modulating serotonin and norepinephrine activity, researchers believe that pregabalin works by inhibiting excitatory inputs to the spinal cord and raising the threshold required to activate nociceptive neurons. Pregabalin also increases delta sleep.
In fibromyalgia studies, pregabalin improved outcomes of pain, fatigue, sleep, and quality of life. In an 8-week placebo-controlled study, patients with fibromyalgia were randomized to treatment with placebo or 1 of 3 pregabalin doses (150 mg, 300 mg, or 450 mg once daily). At the end of the study, the 450 mg dose was associated with a significantly greater reduction in pain severity and fatigue than placebo. In addition, a 50% reduction in pain was reported by about 30% of subjects in the 450 mg dose group compared with fewer than 15% of subjects in the placebo group. Patients treated with 150 mg and 300 mg also demonstrated significant improvement. The 2 higher doses of pregabalin were also associated with significant improvements in sleep quality.
In a second double-blind, placebo-controlled trial, monotherapy with pregabalin was found to be efficacious and safe for treatment of pain associated with fibromyalgia. Subjects were randomized to placebo or pregabalin 300 mg, 450 mg, or 600 mg per day (doses divided and taken twice daily) for 13 weeks. Patients in all of the pregabalin-treated groups showed significant improvement in pain compared with placebo, as well as improvements in assessments of sleep and patients' impressions of their global improvement.
Therapy with pregabalin should be initiated at 75 mg twice daily and increased to 150 mg twice daily over 7 days. Dr. Rospond pointed out that effects can be seen quickly (within 1 week), and recent data demonstrate sustained effectiveness for 6 months or longer. Adverse effects include blurred vision, constipation, dizziness, drowsiness, edema, and weight gain.
Although not FDA-indicated for fibromyalgia, gabapentin has also demonstrated efficacy for fibromyalgia at doses of 1200 mg to 2400 mg per day in 3 divided doses. The most frequent side effects of gabapentin include sedation and dizziness. The incidence of edema with gabapentin appears to be lower than that with pregabalin.
Analgesics
With diffuse pain being the primary symptom of fibromyalgia, it would seem logical to include analgesics in the treatment plan. Tramadol, an atypical opioid, is the only analgesic with demonstrated efficacy in treating fibromyalgia. Not only does tramadol bind to the mu-opiate receptors in the central nervous system, it also inhibits the reuptake of serotonin and norepinephrine. These latter effects on neurotransmitter activity may partially explain tramadol's effectiveness in treating fibromyalgia.
In a randomized, double-blind, placebo-controlled clinical trial, patients with fibromyalgia were first enrolled into an open-label phase and treated with tramadol 50-400 mg per day. Patients who tolerated a perceived benefit from tramadol were then randomized to continued treatment with tramadol or placebo in a 6-week double-blinded phase. The primary efficacy outcome measure was time to exit from the double-blind phase because of inadequate pain relief. Significantly more subjects in the tramadol group completed the double-blind phase compared with those in the placebo group.
Tramadol in combination with acetaminophen is also effective for fibromyalgia. In a 3-month, randomized, double-blind study, tramadol with acetaminophen (37.5 mg tramadol with 325 mg acetaminophen) administered 4 times daily was compared with placebo. At the end of the study, tramadol-treated patients recorded significantly less pain, better pain relief, and greater improvement in FIQ scores than placebo-treated patients.
To minimize dizziness and vertigo, tramadol therapy should be initiated at a dose of 25 mg per day and titrated every 3 days in 25 mg increments until a total dose of 100 mg (25 mg 4 times daily) is achieved. Doses may then be increased incrementally every 3 days to a total of 200 mg (50 mg 4 times daily). Caution must be employed to avoid prescribing more than 4 g of acetaminophen per day to reduce the risk of hepatotoxicity with chronic therapy.
Dr. Rospond reminded the audience that the evidence supporting the effectiveness of nonsteroidal anti-inflammatory agents for fibromyalgia is weak. Additionally, data are insufficient to support the use of narcotic opioids or corticosteroids to reduce fibromyalgia pain. These agents should only be considered when patients are experiencing inadequate benefit or intolerable side effects from other agents.
Miscellaneous Agents
Benzodiazepines and nonbenzodiazepine hypnotics have not demonstrated efficacy in reducing pain or improving function in fibromyalgia. However, drugs within these classes (eg, zolpidem) can be useful as add-on therapies for persistent insomnia.
Preliminary data suggest that pramipexole, a dopamine receptor agonist approved in the United States for the treatment of Parkinson's disease and restless legs syndrome, is also effective for fibromyalgia. In 1 randomized, double-blind, placebo-controlled, 14-week trial, pramipexole 4.5 mg every evening improved outcomes for pain, fatigue, and overall function. Postmarketing reports of pathologic compulsive behaviors (eg, pathologic gambling) have been reported in patients with Parkinson's disease and restless leg syndrome who were taking dopamine agonists. Whether this would occur in patients with fibromyalgia is unknown and deserves further exploration.
Tropisetron is an antiemetic that blocks the serotonin 5-HT3 receptor and increases levels of serotonin. Although not available in the United States, preliminary data suggest efficacy in treating fibromyalgia.
Although a variety of other agents hold promise for fibromyalgia therapy, several have no evidence or only weak evidence to support their use. (Table 4 - see attachment) Recombinant human growth hormone has been tested in women with fibromyalgia and low serum insulin-like growth factor (IGF) levels. In 1 trial, doses of 0.0125 mg/kg were administered subcutaneously once daily (to maintain an IGF-1 level of about 250 ng/mL) for 9 months. At the end of that period, the treated group experienced significant improvement in symptoms (as measured by the FIQ) and signs (measured by the tender point score). Although patients experienced an improvement in functional ability, complete remission of symptoms was not observed. In general there was a lag of about 6 months before patients started to note improvement.
Sodium oxybate is a commercially available preparation of naturally occurring gamma hydroxybutyrate. Doses of 6 g at bedtime have resulted in significant improvements in pain, tenderness, sleep quality, and fatigue. Other agents with no evidence or only weak evidence of efficacy in the management of fibromyalgia include calcitonin, , dehydroepiandrosterone , guaifenesin, 5-hydroxytryptamine, magnesium, melatonin, S-adenosyl-methionine , and thyroid hormones. Further study is needed with all of these agents.
Conclusion
Although fibromyalgia remains a challenging condition to manage, a number of effective therapies are available for patients (Table 5 - see attachment). Only 1 agent, pregabalin, is FDA-approved for the treatment of fibromyalgia, but clinicians should be familiar with other agents that are also effective, as supported by available scientific evidence.
Clinicians can serve as important resources for patients with fibromyalgia. They can help educate patients on the scientific mechanisms of fibromyalgia (ie, involvement of neurotransmitter and nociceptive pathways), the role of nonpharmacologic modalities, and the benefits and risks of available pharmacotherapies. Pharmacists can also assist with selection of nonprescription products for concomitant symptoms such as constipation, headache, and sleep difficulties.
