Fibromyalgia update: Emerging pharmacological treatments

Fibromyalgia syndrome (FMS) is a chronic condition characterized by multiple symptom domains: pain, fatigue, sleep disturbance, mood disturbance, and quality of life and functional impairment.¹ Other common associated conditions and symptoms include irritable bowel syndrome, irritable bladder syndrome (interstitial cystitis), tension and migraine headaches, cognitive dysfunction (“fibrofog”), stiffness, paresthesia, and restless legs syndrome. Until recently, there was no FDA-approved treatment for patients with FMS. Optimal management of FMS involves multimodal treatment approaches that address the variety of symptom domains that patients may experience.

Over the past century, FMS has had several monikers, such as “fibrositis,” but it was not until 1990 that the American College of Rheumatology (ACR) established classification criteria. The criteria defined FMS as a condition in which widespread pain has been present in at least 11 of 18 anatomically specific tender points for at least 3 months.²

The ACR classification criteria were intended to be used for research studies, but increasingly they have been used as diagnostic criteria in practice. This is problematic. Although the tender point examination helps physicians discriminate FMS as a condition characterized by augmented tenderness, an increased number of tender points is seen more frequently in women and is correlated with “distress.” This criterion lacks high specificity and excludes some patients with chronic widespread pain who do not fulfill the tender point criteria but whose pain probably arises from the same pathophysiology.^3,4

To address this and other issues with the 1990 criteria, Wolfe and associates⁵ recently proposed diagnostic criteria, known as the 2010 ACR preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. This criteria set does not rely on a tender point examination. Instead, it uses a clinician-queried checklist of sites that a patient with at least 3 months of chronic widespread pain (CWP) has found painful over the previous week, constituting the CWP index, and a symptom severity scale based on graded severity of fatigue, waking unrefreshed (a surrogate for sleep disturbance), cognitive dysfunction, and other symptom domains characteristic of FMS.

Much remains that is not understood about the pathogenesis and proper classification of FMS, partly because clear-cut biomarkers and objective treatment parameters are lacking, sometimes leading to physician skepticism and patient frustration. However, an increased awareness of the prevalence, clinical pattern, and pathophysiology of FMS-rooted in neural dysregulation, particularly “central sensitization”-is facilitating more prompt diagnosis and appropriate patient care.

In this article, we discuss the epidemiology and pathophysiology of FMS. Then we provide an update on the latest approaches to management of FMS.

EPIDEMIOLOGY
The prevalence of FMS, which occurs primarily in women, is estimated at 2% to 5% of the US population. FMS may exist on its own or be associated with other painful conditions, such as degenerative or inflammatory arthritis and low back pain.⁶ Indeed, the disorder is reported to occur in up to 25% of patients who have rheumatoid arthritis or lupus.⁷

FMS also may occur with other conditions that are considered to be somatic syndromes (ie, symptomatic conditions that do not have demonstrable structural changes and that may share genetic predisposition and pathophysiological mechanisms).⁷ Examples include irritable bowel syndrome, irritable bladder syndrome, and temporomandibular joint syndrome. Some patients ascribe the onset of FMS to specific “triggers,” including viral illness (eg, Lyme disease or hepatitis C), physical trauma, and major emotional stress.⁷

PATHOPHYSIOLOGY:
TARGETS OF THERAPY
In the 1970s, Moldofsky and colleagues⁸ conducted pioneering sleep physiology studies that demonstrated the presence of sleep electrophysiology abnormalities in patients with FMS, suggesting that the pathophysiology of the condition lay in the CNS. Since then, numerous studies have further elucidated central mechanisms.^9-11 Earlier hypotheses attributing the symptoms of FMS to inflammation or a peripheral muscle disorder have largely been set aside.⁶

It has been observed that patients with FMS perceive more pain from nonpainful stimuli (allodynia) and experience greater pain from painful stimuli (hyperalgesia) than do healthy controls.¹² Functional MRI studies conducted by Gracely and associates¹³ have provided dynamic neuroimaging confirmation of this. The increased pain sensitivity of patients with FMS appears to be the result of dysregulation of neuropeptide and neuroreceptor physiology in the ascending and descending spinal cord pain signaling pathways as well as in brain processing centers.

Central sensitization connotes amplified ascending nerve activity and receptor fields, part of which is the phenomenon of temporal summation, or “wind-up,” in which stimuli after an initial pain stimulus are experienced as more intensely painful.⁷ Staud and others have shown this phenomenon to be at least partly the result of dysregulation of the N-methyl D-aspartate (NMDA) receptors in the dorsal horn in patients with FMS. Russell and coworkers¹⁴ noted increased amounts of pronociceptive substance P in the cerebrospinal fluid of patients who had FMS compared with controls. Therefore, treatments known to down-regulate such pronociceptive neuropeptides may be beneficial for FMS.

Kosek and Hansson,¹⁵ as well as other investigators, have noted abnormalities of the descending pain inhibition pathways, or “diffuse noxious inhibitory controls,” in patients with FMS. This may be a location where augmentation of serotonin and norepinephrine has benefit for pain modulation by down-regulating signaling from painful stimuli.¹²

The evidence that patients with FMS have abnormalities in the hypothalamus-pituitary-adrenal axis and autonomic nervous system, dopamine dysregulation, and growth hormone dysregulation-all of which may contribute to pain and other symptom domains of FMS-were reviewed by Pillemer and associates,¹⁶ Wood and colleagues,¹⁷ and Geenen and coworkers,¹⁸ respectively. Other studies have suggested clustering of gene markers related to neurotransmitter function in patients who have FMS compared with controls.⁷

Although widespread pain typically is described as a defining feature of FMS, patients also describe significant fatigue; sleep disturbance; and cognitive dysfunction, such as problems with concentration and memory. Sleep pathophysiology has been well characterized.⁹ Glass¹⁹ has identified defects in working memory, compounded by easy distractibility. More recently, Napadow and colleagues²⁰ described increased connectivity and signaling between a variety of brain centers and the insula, which may partially explain increased non–stimulus-evoked pain experience and also may underlie cognitive dysfunction.

Mood disturbance and psychiatric abnormalities may be major comorbidities in patients with FMS. Studies have suggested that about one-fourth to one-third of patients with FMS have a current diagnosis of depression and that a larger percentage have a history of depression. Other potential psychiatric comorbidities include anxiety, dysthymia, panic disorder, and phobia. Identification of these comorbidities is important to construct optimal combination pharmacotherapy and other treatment modalities.

MANAGEMENT
For optimal FMS management, treatment should be customized to address the symptom domains of specific patients. The most effective treatment approach is multimodal, including both pharmacological and nonpharmacological methods.

Nonpharmacological
treatment
This should be a cornerstone of therapy, especially an approach that focuses on patient and family education, conditioning exercise and, if feasible and appropriate, counseling (eg, cognitive-behavioral therapy [CBT]). Education is important because many patients will have experienced a frustrating diagnosis and treatment path and may have developed distrust about communication with clinicians. In addition, they may have unrealistic expectations about the potential benefit of treatment and, therefore, need an explanation of what is possible. In clinical trials, patient education has resulted in improvement in health satisfaction, pain, pain control, pain behavior, and depression.⁶ CBT has been explored as a treatment for patients with FMS because it has been used effectively to manage other chronic pain conditions.

Some patients also may benefit from complementary and alternative medicine (CAM) approaches to therapy. However, the evidence for the benefit of CAM therapies is not as strong,²¹ and some unproven therapies may be promoted inappropriately.

Additional treatments above and beyond the core treatments for FMS that are appropriate for conditions typically associated with FMS-irritable bowel syndrome, interstitial cystitis, headache, temporomandibular joint syndrome, and restless legs syndrome-can help lower the patient’s overall symptom burden. Teaming up with subspecialists who are familiar with management of these associated conditions, such as gastroenterologists, urologists, neurologists, and dentists, may be indicated.

Pharmacological treatment
An increasing number of controlled trials of pharmacological therapy, particularly neuromodulatory therapy, demonstrate benefit for key clinical domains, including pain, fatigue, sleep, and dyscognition. The first FDA-approved drug for FMS management is pregabalin. Based on its effect on pain, function, and overall patient improvement, pregabalin also is approved for managing pain that results from diabetic neuropathy and postherpetic neuralgia and as adjunctive therapy for seizure disorder.

In the antidepressant class, the mixed serotonin/norepinephrine drugs (eg, duloxetine and milnacipran) are effective and generally well tolerated; for some patients, the older tricyclic agent amitriptyline may be helpful. Analgesics
(eg, tramadol) have shown benefit, although stronger opioid analgesics do not appear to be useful, especially for long-term use. Several other types of medications may be useful in managing specific symptom domains in FMS.

The efficacy of specific medicines typically has been established in monotherapy clinical trials, but most clinicians combine treatments in an effort to achieve additive effects on pain and other symptom domains, such as fatigue and sleep disturbance. In addition, clinicians may take advantage of drug side effects, for example, concentrating the dose of medications that have sedating effects at bedtime to help with disturbed sleep.

By paying attention to what is affecting the patient, clinicians can build gradually, through serial trials of various medications, a treatment regimen that is clinically meaningful. In time, as more medicines in development for FMS obtain approvals, formal trials of rational medication combinations probably will be conducted to determine whether there are additive or synergistic benefits of combination therapy on the one hand or problematic additional adverse effects resulting from the combination on the other.

Effective pharmacological therapies for the symptom domains of FMS include drugs from various classes of neuromodulatory agents. The agents appear to act through effects on cells involved in pain signaling and sleep regulation, as well as in regulation of fatigue, mood, and other elements of the condition.

Tricyclic antidepressants (TCAs). These agents were investigated for management of FMS after the identification of non–rapid-eye-movement sleep disruptions⁸ thought to be related to abnormalities in central serotonergic neurotransmission.²² Tertiary amine TCAs, such as amitriptyline, became the initial candidate antidepressants for FMS therapy because of their effect as serotonin-norepinephrine reuptake inhibitors (SNRIs) that leads to an increased synaptic concentration of these neuropeptides.⁷

Several controlled trials have demonstrated benefit with amitriptyline for pain relief, sleep, and an overall sense of well-being using doses of 25 to 50 mg taken at bedtime. Similar results have been demonstrated with cyclobenzaprine (a TCA officially classified as a muscle relaxant) in doses of 10 to 40 mg. A drawback to using TCAs is the safety and tolerability problems that arise from their anticholinergic, antiadrenergic, antihistaminergic, and quinidine-like effects; compliance is diminished and their long-term utility is limited.⁷ In addition, not all controlled trials have demonstrated benefit with use of TCAs, and their effectiveness may diminish with continued use.²³

Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, citalopram, and paroxetine, are another category of antidepressants that have been evaluated for efficacy in FMS.^7,24,25 The results of several controlled trials of these agents have been mixed. For example, Wolfe and colleagues²⁶ found that a fixed dosage of 20 mg/d of fluoxetine was not superior in effect to placebo in patients with FMS, but Arnold and associates,²⁷ when allowing for adjustable dosing, found that higher dosages of fluoxetine yielded greater symptom benefit. Studies of SSRIs generally have suggested that these agents have less impact on the pain of FMS than do other TCAs.^24,25

Building on the observation of benefit from agents that have dual serotonergic and noradrenergic properties, there have been several large trials of newer SNRIs, which have greater neuroreceptor selectivity than the older TCAs, are better tolerated, and appear to be more potent. The SNRI venlafaxine aids in the management of neuropathic pain and prevention of migraine and tension headaches.²⁸ However, studies of venlafaxine efficacy in FMS have shown conflicting results. Initially, 2 open-label trials showed improvement of FMS symptoms with venlafaxine.^28,29 However, a study that used a fixed low dose of venlafaxine showed improvement in only some pain measurements.²⁹ These data suggest that a higher dose of venlafaxine may be more effective; however, tolerability problems may result.⁶

Duloxetine is now approved in the United States for management of FMS, the pain of diabetic peripheral neuropathy, and depression. Efficacy in several FMS symptom domains-including effects on pain, patient global improvement, and function-has been demonstrated in clinical trials. Path analysis, a logistic regression methodology, demonstrated that most of the drug’s impact on pain was a direct effect and not indirectly mediated through its effect on depression. This finding refutes the common misconception that the positive effects of an antidepressant on FMS symptoms are solely the result of the drug’s antidepressant properties.

Evaluations of sleep in the clinical trials show that duloxetine does not appear to benefit or interfere with sleep quality. Nausea is the most common adverse effect of duloxetine, but typically it is mild and resolves with continued use. Based on the observation that both dosages of 60 mg/d and 120 mg/d had similar effects on pain management,³⁰ the FDA approved a dosage of 60 mg once a day for the treatment of patients with FMS.³¹

Milnacipran, a selective SNRI developed for the management of depression in parts of Europe and Asia, also is now approved in the United States for FMS treatment. The drug acts as both an SNRI, with a greater ratio of norepinephrine to serotonin augmentation, and a mild NMDA inhibitor.

Controlled trials of patients with FMS taking twice-daily doses of 50 mg or 100 mg of milnacipran have shown statistically significant benefit in multiple symptom domains, including pain, patient global improvement, fatigue, cognition, and physical functioning.³² Milnacipran, like duloxetine, had little effect on sleep quality. The most common adverse effects are nausea and headache, which tend to resolve as the patient continues with treatment. In 2009, the FDA approved milnacipran for the management of FMS in both the 50-mg twice-daily and 100-mg twice-daily dosages.³¹

Antiepileptic drugs. Drugs originally developed as antiepileptics also have been studied for efficacy and safety in patients with FMS.³³ Pregabalin binds to the α₂-δ auxiliary protein associated with voltage-gated calcium channels and modulates neuronal calcium influx. The result is a reduction of release of several neurotransmitters, such as glutamate and substance P, that play a role in pain processing.

Pregabalin has been approved for management of diabetic neuropathy, postherpetic neuralgia, and seizure disorder. The efficacy of pregabalin in FMS was first established in an 8-week controlled trial of 529 patients.³⁴ A 450-mg total daily dose yielded improvements in pain, patient global impression of improvement with therapy, sleep disturbance, fatigue, and health-related quality of life; improvement was seen in some of the measures with 300 mg/d of pregabalin.

A pivotal phase 3 trial of pregabalin in FMS confirmed these observations, including efficacy in the 3 key domains of pain, patient global improvement, and function,³⁴ and supported the longer term durability of effect over 6 months.³⁵ Adverse effects experienced by some patients included dizziness and sedation, but these adverse events have tended to improve and resolve as the drug is used. Weight gain, the mechanism for which is uncertain, has been a troublesome adverse effect for some patients. On the basis of these results, the FDA granted approval for the use of pregabalin for the management of FMS in June 2007.

A single controlled trial of gabapentin showed efficacy in multiple FMS symptom domains.³⁶ Although this agent is mechanistically similar to pregabalin, its pharmacokinetic and pharmacodynamic profile is not as favorable.

Sedative-hypnotics. These agents may help restore disrupted or nonrestorative sleep in patients with FMS. Sodium oxybate, a sodium salt of γ-hydroxybutyrate (a precursor of γ-aminobutyric acid), is approved for management of narcolepsy. In an 8-week randomized controlled trial, patients taking sodium oxybate, 4.5 or 6 g per night, showed significant gains in pain, global improvement, Fibromyalgia Impact Questionnaire total score, fatigue, and sleep polysomnographic changes.³⁷ These results have been confirmed in phase 3 trials. Thus far, however, this agent has not been approved by the FDA for the treatment of FMS.

Other sedative hypnotics studied in patients with FMS are the short-acting nonbenzodiazepine sedatives zolpidem and zopiclone.⁷ Use of these drugs improved patients’ sleep but not their pain; they are potentially useful adjunctive treatment medications.

Analgesics. These agents have been used in the attempt to mitigate pain, the primary symptom in patients with FMS. A clinic survey found that about 14% of patients with FMS are treated with opioid analgesics.³⁸ However, the results of a double-blind, placebo-controlled study of intravenous morphine did not show a reduction in pain intensity.³⁹

Tramadol, a mild opioid analgesic, was well tolerated and effective in patients with FMS.⁴⁰ A trial of a combination of tramadol and acetaminophen found 50% pain improvement in 35% of the treatment group, compared with 18% of the placebo group.⁴¹ NSAIDs have no effect when used alone, but they may be modestly helpful when combined with a TCA.⁴²

Dopamine agonists. These agents, approved for management of Parkinson disease, have been explored for efficacy in FMS. Pilot data for ropinirole showed efficacy in managing FMS pain. In a controlled trial of pramipexole, 4.5 mg/d, pain, fatigue, function, and patient global status improved in those who were allowed to continue background medicines for FMS.⁴³ This medication has not been subjected to rigorous multicenter controlled trials and is not going to be FDA-approved for FMS.

Other agents. A variety of other drugs have been explored as potential treatments for patients with FMS symptoms. Tizanidine, a centrally acting α₂-adrenergic agonist, is used for management of muscle spasticity associated with multiple sclerosis and stroke. Treatment with 4 mg of tizanidine taken at bedtime or 24 mg taken during the day improved sleep, pain, and physical function and reduced levels of substance P in cerebrospinal fluid after 8 weeks.¹⁴

Growth hormone, which has been observed to be diminished in FMS, was found to improve overall symptoms and tender point count after 9 months, although this treatment approach has not been further developed because of the impracticality of frequent injections.⁴⁴ Tropisetron is a serotonin receptor (5-HT₃) antagonist that was shown to be of benefit in FMS when given as an intravenous bolus but not orally; again, the need for parenteral administration rendered this agent poorly feasible for development.⁴⁵ Oral 5-hydroxytryptophan (5-HTP), a prodrug for serotonin, improved tender point count, subjective pain, stiffness, sleep patterns, and anxiety.²⁵

In addition to drugs, 2 forms of electromagnetic wave therapy devices, transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), are being developed to manage pain and are being tested in FMS.^46,47 The tDCS device modifies brain activity noninvasively; it improved pain and physical function in patients with FMS.⁴⁶ The rTMS device also improved pain in FMS.⁴⁷ These devices currently are in further development as adjunctive therapy for pain management.

CONCLUSION
Comprehensive management of patients with FMS includes coupling of medications with nonpharmacological approaches, such as education, counseling, exercise, and CAM. Clinicians who treat patients with FMS ideally work as part of a team of care providers focused on helping patients return to a more functional and symptom-reduced state.

Primary care physicians are in an ideal position to first identify the possibility of FMS in a patient, perhaps initiate appropriate testing to rule out other diagnoses in the differential, educate the patient and his or her family, and begin initial therapy approaches. The patient often can benefit from more education from a specialist versed in FMS care, as well as treatment regimens tailored to the various symptom domains that he experiences. Ongoing comanagement by both the primary care physician and the specialist team provides optimal avenues for communicating with the patient and caregivers and for fine-tuning of treatment; dealing with medication tolerability issues; and navigating issues that impact family, social, and work relationships.

References:

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