Treatment of Fibromyalgia
Progress in the understanding of fibromyalgia has led to more therapeutic
options for patients with this condition. Investigators are examining the
utility of newer medications as well as nonpharmacologic interventions in
controlled trials (Figure 8). Clinical-based evidence advocates a multifaceted
program emphasizing education, certain medications, exercise, and cognitive
therapy.[62]
Figure 8. An example of dually focused approach, involving pharmacologic and
nonpharmacologic therapies for the treatment of fibromyalgia. Diagnostic
Labeling Once a physician rules out other potential disorders, an important and
sometimes controversial step in the management of fibromyalgia is asserting the
diagnosis. Despite some assumptions that being "labeled" with fibromyalgia may
adversely affect patients, a study by White and colleagues[54] indicated that
patients had significant improvement in health satisfaction and symptoms after
being "labeled." Nonetheless, in certain select individuals, ie, adolescents,
young adults, or overtly anxious persons, the preferred route may still be to
not label. Regardless, diagnosis confirmation ideally should be coupled with
patient education, an intervention shown to be effective in randomized,
controlled trials.[62]
Pharmacologic Therapy The majority of fibromyalgia clinical trials have
involved antidepressants, though other classes of drugs have been tested as well
(Table 3). Trials studying the oldest class of agents, tricyclic antidepressants
(TCAs), are most abundant, though several recent studies have focused on
selective serotonin reuptake inhibitors (SSRIs) and "atypical antidepressants,"
a class that includes dual reuptake inhibitors and monoamine oxidase inhibitors
(MAOIs).
Table 3. Pharmacologic Therapies Strong Evidence Modest Evidence
Weak Evidence Not Shown to Be Effective Tricyclics Tramadol Growth hormone
Opioids amitriptyline cyclobenzaprine Dual-reuptake inhibitors
Serotonin reuptake inhibitors 5-hydroxytryptamine NSAIDs Venlafaxine
Duloxetine Milnacipran Alpha-2-delta ligands (eg, pregabalin,
gabapentin) Tropisetron Corticosteroids Dopamine agonists
S-adenosyl-L-methionine (SAMe) Benzodiazepine and nonbenzodiazepine hypnotics
Melatonin Guaifenesin Dehydroepiandrosterone
NSAIDs = nonsteroidal anti-inflammatory drugs Tricyclic antidepressants. The
most frequently studied pharmacologic therapy for fibromyalgia is low doses of
tricyclic compounds. Most TCAs increase the concentrations of serotonin and/or
norepinephrine (noradrenaline) by directly blocking their respective reuptake
(Figure 9). The effectiveness of TCAs, particularly amitriptyline and
cyclobenzaprine, in treating the symptoms of pain, poor sleep, and fatigue
associated with fibromyalgia is supported by several randomized, controlled
trials.[63] Tolerability is a problem but can be improved by beginning at very
low doses (eg, 10 mg of amitriptyline), giving the dose a few hours before
bedtime, and very slowly escalating the dose.
Figure 9. Relative activity on serotonin and norepinephrine reuptake among
antidepressants. Selective serotonin reuptake inhibitors (SSRIs). Because of a
generally better side-effect profile, newer antidepressants, ie, SSRIs, are
frequently used in fibromyalgia. The SSRIs fluoxetine, citalopram, and
paroxetine have each been evaluated in randomized, placebo-controlled
trials.[62,64-66] In general, the results of studies of SSRIs in fibromyalgia
have paralleled the experience in other pain conditions. The newer, "highly
selective" SSRIs, eg, citalopram, seem to be less efficacious than the older
SSRIs, which have some noradrenergic activity at higher doses.[67]
Dual reuptake inhibitors. Because TCAs and high doses of certain SSRIs (ie,
fluoxetine and sertraline, which have the most balanced reuptake inhibition) are
the most effective analgesics, many investigators have concluded that
dual-receptor inhibitors, such as serotonin-norepinephrine (NE) and NE-serotonin
reuptake inhibitors (SNRIs and NSRIs) may be of more benefit than pure
serotonergic drugs.[67] These drugs are pharmacologically similar to some TCAs
in their ability to inhibit the reuptake of both serotonin and NE, but differ
from TCAs in being generally devoid of significant activity at other receptor
systems. This selectivity results in diminished side effects and enhanced
tolerability. The first available SNRI, venlafaxine, has data to support its use
in the management of neuropathic pain, and retrospective trial data demonstrated
that this compound is also effective in the prophylaxis of migraine and tension
headaches.[68] Two studies in fibromyalgia have had
conflicting results, with the one that used a higher dose showing efficacy.[62]
Two new SNRIs, milnacipran and duloxetine, have undergone recent, multicenter
trials that showed them to be effective in a number of outcome variables for
fibromyalgia.[69,70] In the study evaluating milnacipran,[69] 125 patients were
randomized to receive placebo or milnacipran for 4 weeks of dose escalation (to
200 mg/day) followed by 8 weeks of constant dose. At the end of the study, 37%
of the milnacipran-treated patients reported at least a 50% reduction in pain
intensity, compared with 14% of those receiving placebo (P < .05). Further, 75%
of the milnacipran-treated patients reported overall improvement for symptoms
such as pain, fatigue, depressed mood, and sleep, compared with 38% of those
receiving placebo (P < .01). In the trial of duloxetine,[70] 207 patients were
randomized to receive duloxetine (60 mg twice a day) or placebo for 12 weeks. At
the end of the study, participants treated with duloxetine had decreased
self-reported pain and stiffness and a reduced
number of tender points, compared with those receiving placebo. In both
studies, benefits were shown to be independent of the drug effect on mood, thus
suggesting that the analgesic and other positive effects of this class of drugs
in fibromyalgia are not simply due to their antidepressant effects.
Other central nervous system acting drugs. Antiepileptic drugs are widely used
in the treatment of various chronic pain conditions, including postherpetic
neuralgia and painful diabetic neuropathy.[71] In June 2007, pregabalin, an
alpha-2-delta ligand, became the first drug approved by the US Food and Drug
Administration (FDA) specifically for fibromyalgia. A randomized,
double-blinded, placebo-controlled trial[72] demonstrated the efficacy of
pregabalin against pain, sleep disturbances, and fatigue compared with placebo.
In the 8-week trial of 529 fibromyalgia patients, patients receiving pregabalin
450 mg/day had significantly reduced severity of pain, and those receiving both
450 mg and 300 mg/day had significant improvements in sleep quality, fatigue,
and global measures of change. The most common side effects were dizziness and
somnolence. Pregabalin is approved at doses of either 300 or 450 mg/day.
Gabapentin, a compound with similar pharmacology to pregabalin, is
specifically indicated for the treatment of postherpetic neuralgia, and studies
also support its use in fibromyalgia as well as in the symptomatic treatment of
a variety of pain states as well as headache prophylaxis.[71,73] Another
antiepileptic compound, clonazepam, has demonstrated efficacy in treating
temporomandibular disorder and associated jaw pain, is useful in the treatment
of restless leg syndrome, and may be of value in fibromyalgia.[71]
Sedative-hypnotic compounds are widely used by fibromyalgia patients. A
handful of studies have been published on the use of certain nonbenzodiazepine
hypnotics in fibromyalgia, such as zopiclone and zolpidem. These reports have
suggested that these agents can improve the sleep and, perhaps, fatigue of
fibromyalgia patients, though they had no significant effects on pain. However,
gamma-hydroxybutyrate (also known as sodium oxybate), a precursor of GABA with
powerful sedative properties, was shown to be useful in improving fatigue, pain,
and sleep architecture in patients with fibromyalgia.[74] Note, though, that
this agent is a scheduled substance due to its abuse potential.
Pramipexole is a dopamine agonist indicated for Parkinson's disease that has
shown utility in the treatment of periodic leg movement disorder.[75] Recent
studies suggest that this compound may improve both pain and sleep in
fibromyalgia patients.[76]
Tizanidine is a centrally acting alpha-2 adrenergic agonist approved by the
FDA for the treatment of muscle spasticity associated with multiple sclerosis
and stroke. The literature suggests that this agent is a useful adjunct in
treating several chronic pain conditions, including chronic daily headaches and
low back pain. A recent trial[77] reported significant improvements in several
parameters in fibromyalgia, including sleep, pain, and measures of quality of
life. Of particular interest was the demonstration that treatment with
tizanidine resulted in a reduction in substance P levels within the central
spinal fluid of patients with fibromyalgia.
Analgesics. There have been no adequate, randomized, controlled clinical
trials of opiates in fibromyalgia, and many in the field (including the author
of this review) have not found this class of compounds to be effective in
anecdotal experience. However, one possibility is tramadol, a compound that has
some opioid activity (weak mu agonist activity), combined with serotonin/NE
reuptake inhibition. This compound does appear to be somewhat efficacious in the
management of fibromyalgia as both an isolated compound and as fixed-dose
combination with acetaminophen.[75]
A large number of fibromyalgia patients use NSAIDs and acetaminophen. Although
numerous studies have failed to confirm the effectiveness of NSAIDs alone as
analgesics in fibromyalgia, there is limited evidence that patients may
experience enhanced analgesia when treated with combinations of NSAIDs and other
agents. This phenomenon may be a result of concurrent "peripheral" pain
conditions (ie, due to damage or inflammation of tissues as with osteoarthritis
and rheumatoid arthritis) that may be present and/or that these comorbid
peripheral pain generators might lead to worsening of "central" pain.
Nonpharmacologic Therapies The 2 best-studied nonpharmacologic therapies are
cognitive-behavioral therapy and exercise (Table 4). Both of these therapies
have been shown to be efficacious in the treatment of fibromyalgia, as well as
for a plethora of other medical conditions.[62,78] Both of these treatments can
lead to sustained (eg, greater than 1 year) improvements and are very effective
when an individual complies with therapy.
Table 4. Nonpharmacologic Therapies Strong Evidence Modest Evidence
Weak Evidence Not Shown to Be Effective Cardiovascular exercise Strength
training Acupuncture Tender (trigger)-point injections Cognitive-behavioral
therapy Acupuncture Chiropractic Flexibility exercise Patient education
Hypnotherapy Manual and massage therapy Multidisciplinary therapy
Biofeedback Electrotherapy Balneotherapy Ultrasound
Alternative therapies have been explored by patients managing their own
illness, as well as by healthcare providers. As is the case in other diseases,
there are few controlled trials to advocate their general use. Trigger-point
injections, chiropractic manipulation, acupuncture, and myofascial release
therapy are among the more commonly used modalities that have achieved varying
levels of success. Two randomized, sham-controlled trials of acupuncture showed
no difference between the 2 groups.[79,80] A usual-care comparison group was not
studied. There is some evidence that the use of alternative therapies give
patients a greater sense of control over their illness. In instances where this
sense of control is accompanied by an improved clinical state, the decision to
use these therapies is between physicians and patients themselves.
A consensus Approach to The Management of Fibromyalgia Recently the European
League Against Rheumatism (EULAR) developed evidence-based recommendations for
the management of fibromyalgia. Overall, 9 recommendations were developed on the
basis of systematic review and expert consensus. The categories of treatment
included antidepressants, analgesics, and "other pharmacologicals"; exercise;
cognitive-behavioral therapy; education; and dietary interventions. [81] Recent
studies recommend a multimodal approach to treatment involving individualized,
evidence-based pharmacotherapy and self-management. Treatment goals should
include the improvement of symptoms, primarily pain and sleep, and the promotion
of positive health behaviors with the aim of improving physical function and
emotional well-being.[82]
Prognosis of Fibromyalgia The prognosis of fibromyalgia depends largely on
where the individual falls on a continuum. On one end of the continuum are
individuals in the population with chronic widespread pain or individuals with
fibromyalgia who are seen in primary care. Their prognosis is quite good.[83,84]
On the other end are individuals with fibromyalgia seen in tertiary care
settings, who do quite poorly.[85] In the study of patients in tertiary care
settings, there was little change in symptoms over time and no significant
change in health satisfaction, symptoms, or functional disability.
In regard to function in fibromyalgia, studies have reported varying
disability rates from 9% to 44%.[84,86,87] Disability has been most strongly
associated with functional and work status, pain, mood disturbances, coping
ability, depression, pending litigation, and educational background.
General Considerations Management strategies for fibromyalgia are similar to
those for other chronic illnesses, whereby empathetic healthcare providers
should develop a partnership with their patients. At one end of the continuum,
there are some individuals with fibromyalgia who respond to a single medication
or a graded, low-impact exercise program. At the other end of the continuum are
tertiary care patients with high levels of distress, who have no sense of
control of their illness, little social support, and have looked to disability
and compensation systems to try to solve their problem. For this individual, and
many in between, multimodal programs that integrate nonpharmacologic (especially
exercise and cognitive-behavioral therapy) and pharmacologic therapies are
required.
Supported by an independent educational grant from Forest Pharmaceuticals




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