Download Update on Fibromyalgia Therapy

REVIEW
Update on Fibromyalgia Therapy
Micha Abeles, MD,a Bruce M. Solitar, MD,b,c Michael H. Pillinger, MD,b,c Aryeh M. Abelesa,b,c
a
Division of Rheumatology, Department of Medicine, The University of Connecticut School of Medicine, Farmington; bDivision
of Rheumatology, Department of Medicine, New York University School of Medicine/NYU Hospital for Joint Diseases, New York;
c
New York Harbor VA Healthcare System, New York Campus; New York.
ABSTRACT
Primary fibromyalgia, a poorly-understood chronic pain syndrome, is characterized by widespread musculoskeletal pain, nonrestorative sleep, fatigue, psychological distress, and specific regions of localized
tenderness, all in the absence of otherwise apparent organic disease. While the etiology of fibromyalgia is
unclear, accumulating data suggest that disordered central pain processing likely plays a role in the
pathogenesis of symptoms. Although various pharmacological treatments have been studied and espoused
for treating fibromyalgia, no single drug or group of drugs has proved to be particularly useful in treating
fibromyalgia patients as a whole, and only one drug to date has earned U.S. Food and Drug Administration
approval for treating the syndrome in the United States. This review critically and systematically evaluates
clinical investigations of medicinal and nonmedicinal treatments for fibromyalgia dating from 1970 to 2007.
© 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, 555-561
KEYWORDS: Complementary therapy; Fibromyalgia; Fibrositis; Pharmacotherapy
Fibromyalgia is characterized by widespread musculoskeletal pain, nonrestorative sleep, fatigue, psychological distress, and specific regions of localized tenderness, all in the
absence of otherwise apparent organic disease. The etiology
of fibromyalgia is unclear, although accumulating data suggest that disordered central pain processing plays a role in
its pathogenesis.1 While numerous controversies surround
the cause and nature of fibromyalgia, few clinicians would
disagree that fibromyalgia patients are in need of effective
treatment.
Despite the various pharmacotherapies studied and espoused for treating fibromyalgia, only one drug has earned
US Food and Drug Administration (FDA) approval for
treating the syndrome (pregabalin, in June 2007). Nevertheless, scores of drugs are used for the treatment of fibromyalgia, with varying success. One 5-year prospective survey
of 214 patients with fibromyalgia from 114 rheumatology
practices revealed a total of 74 different medications being
used for treatment, suggesting that no specific drug or class
of drugs is particularly useful for fibromyalgia patients as a
group.2
Requests for reprints should be addressed to Aryeh M. Abeles, MD,
New England Musculoskeletal Institute, Medical Arts & Research Building, UConn Health Center, 263 Farmington Avenue, Farmington, CT
06030-5352.
E-mail address: [email protected]
0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2008.02.036
Given the controversial nature of fibromyalgia, it is not
surprising that physicians continue to debate which treatments are useful. While several recent reviews conclude that
there is “strong evidence”3 to support the use of a variety of
medications and nonpharmacologic approaches to fibromyalgia, and that “symptoms can be controlled to a moderate
degree with various treatments,”4 a long-term, multicenter
outcomes study has refuted these conclusions, noting that
despite treatment, individuals followed for up to 7 years
demonstrated no change in symptoms.5 That study might
itself have been skewed, because its data were culled from
tertiary care rather than a community setting,6 and community fibromyalgia patients appear to have better prognoses
than those seen in specialty clinics.7 However, as both the
fibromyalgia criteria and many therapeutic trials to date
have been based on patients in tertiary centers, we are left
with conflicting data sets on the value of fibromyalgia treatment. In addition, many therapeutic trials for fibromyalgia
have been small or not well controlled, with results that can
be of limited use.
One difficulty of assessing therapeutic options for an
individual patient is that many clinical trials have not accounted for the heterogeneity of fibromyalgia.8,9 The presence of co-morbidities, such as depression, may independently predict a poor response to treatment.9,10 In addition,
nondrug treatment approaches, considered by many physi-
556
The American Journal of Medicine, Vol 121, No 7, July 2008
vance. The remaining 45 research articles were included
cians to be among the most useful fibromyalgia treatments,
in the analysis. Our review was not funded.
are frequently discordant with patient preferences.11 Adding
to the confusion of how to appropriately manage the syndrome, the Outcome Measures in Rheumatology 7 workPHARMACOLOGICAL TREATMENTS
shop concluded that when it comes to fibromyalgia therapy,
there is “little standardization of
Tricyclic Agents
an approach to trials or of outThe
tricyclic antidepressants were
come measures used.”12 In this arthe
first
drugs to be intensively
CLINICAL SIGNIFICANCE
ticle, we attempt to create a modistudied in fibromyalgia. Tricyclic
cum of clarity in the current
● Fibromyalgia is a heterogeneous pain
antidepressants increase synaptic
landscape, by providing a critical
concentrations of both serotonin
syndrome of unclear etiology. Review of
review of the evidence for various
and norepinephrine in the central
the literature suggests no single thertreatments of fibromyalgia.
nervous system; increased availapy is broadly efficacious.
The authors reviewed the
ability of these neurotransmitters
● Medications showing some benefit in
treatments of fibromyalgia by
reduces pain signaling. Amitriptysearching the PubMed database
the treatment of fibromyalgia include
line is the tricyclic antidepressant
for English-language reports of
antidepressants and voltage-gated Ca⫹⫹
most extensively studied. Shortclinical trials and meta-analyses
channel blockers.
term studies indicate benefit in up
addressing fibromyalgia treatto one third of patients13-15; if ef● Evidence suggests that some complemenment, published between 1970
fective, benefit is usually evident
tary therapies also might be beneficial.
and 2007. The main search terms
within the first 2 weeks of therwere fibromyalgia and fibrositis,
apy.16 Long-term studies have
● Clinical experience suggests multiin combination with treatment,
been less promising, however, and
modal therapy provides greater benefit
clinical trials, and pharmacoprospective studies have not shown
than individual interventions, but this
therapy. Secondary search terms
any prolonged beneficial effect.17 In
hypothesis has yet to be rigorously
included exercise, alternative therapy,
one study, initial improvement
tested.
and cognitive-behavioral thernoted at 6 to 12 weeks was lost at 26
apy. These search terms resulted
weeks.17 When employed, amitripin the identification of 409 retyline dosing should start at 10 mg,
ports for possible inclusion. After an initial triage by one
because anticholinergic side effects are more likely at higher
of the authors (AMA), selecting for studies conducted as
doses. Studies suggest that increasing the dose to 25-50 mg can
randomized control trials investigating specific intervenbe effective in short-term trials.13,14 The tricyclic antideprestions and their effects on improved outcomes, 131 artisant nortriptyline has a better side-effect profile than amitripcles remained and were scored semiquantitatively by
tyline and also might be useful, although it requires slightly
each of the 4 authors. Each author scored each report on
higher dosing.18
a scale of 0-3 in 2 overarching domains: 1) the quality of
Cyclobenzaprine shares its tricyclic structure with ammethodology (authors were instructed to consider
itriptyline and nortriptyline but does not function as an
whether studies were randomized double-blind control
antidepressant. Instead, cyclobenzaprine acts at the brain
trial vs randomized open label control trials, large vs
stem to induce skeletal muscle relaxation.19 The idea that
small enrollment, independent vs industry-supported,
muscle spasm may play a role in fibromyalgia pain (delength of study, and appropriateness of outcomes measpite electromyographic studies showing no evidence of
sures); and 2) the relevance of the study to the illness of
spasm) led to investigations of cyclobenzaprine.20-22
fibromyalgia (authors were instructed to consider paramShort-term (12-week) studies suggest that 10-40 mg per
eters such as the degree of efficacy reported, degree to
day of cyclobenzaprine reduces fibromyalgia pain and
which the drug is currently used in practice, degree to
sleep disturbance,20,22 although in one cross-over study,
which the study was unique in examining a particular
there was no effect on pain.23 Moreover, long-term studagent, and level of attention that the study has subseies have not shown any advantage of cyclobenzaprine
quently received among practitioners). The maximum
over placebo.17 A meta-analysis of cyclobenzaprine treatscore any article could receive from a single evaluator
ment of fibromyalgia found only 5 articles of adequate
was 6, and the maximum total score any article could
quality to include in the study,24 and concluded that some
receive from all authors combined was 24. All manushort-term benefit may result with cyclobenzaprine use,
scripts receiving total scores of ⬎16 were considered for
but that the number needed to treat in order for one
inclusion by the authors in consensus discussions; a total
patient to experience a benefit was 5. Adding to the
of 55 manuscripts were discussed. Of these, 10 additional
difficulty of interpreting cyclobenzaprine studies is the
manuscripts were excluded, based on a high degree of
high incidence of side effects (85%), which makes blinding difficult.
author discrepancy with regard to study quality or rele-
Abeles et al
Fibromyalgia Therapy
Newer Anti-Depressants
Selective serotonin reuptake inhibitors (SSRIs) also might
theoretically be useful because of their ability to increase
serotonin availability at the neuronal synapse. While initial
reports found no improvement in pain symptoms with fluoxetine,25 follow-up studies suggested that this SSRI was as
effective as amitriptyline. The 2 medications combined
showed greater efficacy than either alone.26 A more recent
placebo-controlled 12-week study using a more flexible
fluoxetine-dosing regimen (up to 80 mg/day) demonstrated
a reduction in pain regardless of effect on depression.27 In
addition, both fluoxetene and amitriptyline appear to improve anaerobic, but not aerobic, performance among female fibromyalgia patients.28 Although other SSRIs are
regularly used in clinical practice, studies of these various
drugs have been limited, lacking, or inconclusive.29,30 For
instance, a recent 12-week study investigating the efficacy
of extended-release paroxetine (doses ranging from 12.5 mg
to 62.5 mg daily) demonstrated that while paroxetine improved Fibromylagia Impact Questionnaire (FIQ) scores vs
placebo, it did not improve pain scores.30
Serotonin-norepinephrine reuptake inhibitors (SNRIs, or
dual-reuptake inhibitors) may have greater antinociceptive
properties than pure SSRIs. Short-term (12 weeks) studies
of SNRIs indicate benefit to their use.31 In one double-blind
trial comparing duloxetine with placebo, patients receiving
duloxetine had significant overall improvement in their FIQ
scores, although not on the FIQ subscales of pain or fatigue.
Secondary outcome measures, including Brief Pain Inventory scores, also showed statistically significant improvements. Common side effects included insomnia, dry mouth,
constipation, increase in heart rate, and elevated aspartate
transaminase, creatine phophokinase, and cholesterol. Effective doses ranged from 60 mg daily to 60 mg twice a
day.31
Milnacipran (unavailable in the US), a SNRI that is
somewhat selective for norepinephrine reuptake inhibition,
also has been studied. A 12-week study found that milnacipran significantly improved both global assessment and FIQ
pain visual analogue scale scores. Despite randomization,
mood disorders were much more common in the placebo
group. Side effects were similar to those seen with duloxetine. Milnacipran 100 mg twice daily was more effective
than at 200 mg once a day.32
Other Central Nervous System-Acting Agents
Pregabalin was originally FDA-approved for diabetic neuropathy and postherpetic neuralgia, but in June 2007 also
was approved for the treatment of fibromyalgia. It disrupts
neuronal signaling by binding to the ␣-2-␦ subunit of voltage-gated calcium channels in the central nervous system.
An 8-week double-blind placebo-controlled trial studied 3
fixed doses of pregabalin (150 mg/day, 300 mg/day, and
450 mg/day).33 The highest dose (450 mg/day) was significantly more effective than placebo in reducing pain score
(48.4% vs 27.1% response, respectively) at 8 weeks. Pre-
557
gabalin also was associated with decreased fatigue, improved sleep and health-related quality of life. Common
side effects included dizziness (49.2%) and somnolence
(28%). No long-term data are yet available, although an
as-yet unpublished study demonstrated that, over 6 months,
pregabalin retained its effectiveness in pregabalin-responders. The study was unusual in that it randomized patients
who had been pregabalin-responders (⬎50% improvement
on visual analogue scale) in an open-label phase to receive
either pregabalin or placebo in the double-blinded portion of
the study; the primary endpoint of the double-blinded study
was time to loss of efficacy. By study’s end, 61% of placebo
patients had lost their therapeutic response, compared with
32% of those who continued with pregabalin.34
Gabapentin is FDA-approved as an anticonvulsant and
for postherpetic neuralgia, and is frequently prescribed for
diabetic neuropathy and other chronic pain conditions. Although structurally related to gamma-aminobutyric acid,
gabapentin does not, in fact, bind to gamma-aminobutyric
acid receptors, but instead appears to inhibit the same voltage-gated calcium channels as pregabalin. In a 12-week
randomized controlled trial, gabapentin was statistically
more effective than placebo in improving pain scores (51%
vs 31%, clinically significant improvement defined as
⬎30% improvement in pain severity), sleep quality, and
fibromyalgia impact questionnaire scores. The dose range
was between 1200 and 2400 mg per day, with an average of
1800 mg. No serious adverse events were noted in the
gabapentin-treated groups. The most common side effects
were dizziness, sedation, and lightheadedness.35
Anti-Inflammatories
While the use of nonsteroidal anti-inflammatory drugs for
fibromyalgia is a fairly common practice,5 little objective
evidence is available upon which to assess the efficacy of
these agents. In one double-blind, placebo-controlled trial,
ibuprofen was no better than placebo.36 Similarly, naproxen
led to minor but insignificant improvement in symptoms.14
One trial of corticosteroid use in fibromyalgia found steroids to be inefficacious.37
Pure Analgesics
Despite their employment in clinical practice, no short- or
long-term data are available to inform the use of pure
opiates in fibromyalgia. In contrast, some studies support
the use of the mixed opiate agonist tramadol. Tramadol is a
centrally acting synthetic opioid analgesic that binds to the
␮-opioid receptors and also weakly inhibits norepinephrine
and serotonin reuptake.38 In a 91-day, multicenter, randomized controlled trial evaluating tramadol plus acetaminophen in fibromyalgia, the primary endpoint was cumulative
time to discontinuation of drug. A large number of dropouts
occurred in both treatment arms, but fewer in the active
treatment group (48% in the active treatment vs 62% in
the placebo arm). Tramadol/acetaminophen combinationtreated patients experienced reduced pain, as measured on a
558
visual analogue scale, compared with patients in a placebo
arm, but it is questionable whether the reported reduction
was clinically significant.39 However, another tramadol/
acetaminophen study investigating health-related qualityof-life measures in moderate-to-severe fibromyalgia also
showed improvement in the active treatment group, compared with controls.40
Miscellaneous Oral Medications
Despite its continuing prominence on Internet websites,
guaifenesin was no more effective than placebo in a formal
study.41 A reported benefit of combining alprazolam and
ibuprofen was based on a response in 7 of 15 patients using
this combination, compared with 4 of 14 patients responding to placebo (in a study underwritten by the manufacturer
of those products)42; no large studies of benzodiazepines
have been performed. The hypnotic zolpidem improved
sleep but not pain in fibromyalgia patients.43 Studies of
malic acid and chlomipramine have a number of shortcomings, including small subject numbers and lack of confirmatory studies.44,45
NONPHARMACOLOGICAL INTERVENTIONS
A recent review by Goldenberg suggested “strong evidence
for efficacy” for a variety of nonmedicinal interventions,
including cardiovascular exercise, cognitive behavioral
therapy, patient education in group format, and multidisciplinary therapy, as well as “moderate evidence for efficacy”
for a number of other adjunctive treatments.3 In contrast to
the Goldenberg review, 2 other systematic reviews came to
less sanguine conclusions about the value of nonpharmacological interventions. Karjalainen et al46 analyzed studies of
multidisciplinary rehabilitation for fibromyalgia. Seven
studies met the authors’ inclusion criteria, although none
were considered “high quality.” Karjalainen concluded that
there was little evidence for the effectiveness of a multidisciplinary approach but that high-quality prospective trials
are needed. Sim and Adams47 reviewed all randomized
controlled trials of nonpharmacologic fibromyalgia interventions from 1980 to 2000.47 Most had small sample size,
leading to low statistical power and a high probability of
type II error. The authors concluded that most interventions
showed marginal efficacy but that, owing to the poor quality
of the studies, no meaningful conclusions could be derived.
Nevertheless, the authors felt that combination approaches
seemed to result in better outcomes than single-approach
interventions.
Presently, aerobic exercise is widely recommended for
fibromyalgia, based on the belief that patients with fibromyalgia are not aerobically fit, and that lack of aerobic
fitness contributes to pain.48 The concept that fibromyalgia
and poor physical fitness are intertwined was originally
based on the resistance of 3 aerobically fit male volunteers
to developing fibromyalgia-like symptoms despite stage IV
sleep deprivation.49 From this finding, a hypothesis evolved
asserting that sedentary lifestyle results in muscle decondi-
The American Journal of Medicine, Vol 121, No 7, July 2008
tioning and a greater risk of muscle microtrauma, in turn
leading to increased pain.50 The hypothesis was tested in a
study that compared a flexibility exercise program with
cardiovascular training51; no significant differences were
found between groups with regard to pain intensity scores.
Other studies also suggest that physical training does not
significantly contribute to the reduction of pain, improvement of psychological symptoms, or functional disability.52
On the other hand, a combined cardiovascular fitness training and flexibility program provided significantly greater
improvement than a psychologically based muscle relaxation technique.53 Recent studies indicate that isometric
exercise reduces mechanical pain thresholds (ie, induces
pain) in fibromyalgia patients, in contradistinction to normal
controls.54 Some clinicians suggest that this observation
reflects a “transition problem”—that is, fibromyalgia patients may not benefit from exercise unless they can first be
brought to a level of minimal exercise capacity without
exacerbating their symptoms. Water-based exercise is better
tolerated by fibromyalgia patients and may therefore be of
particular benefit as an initial regimen. Short-term studies of
aquatherapy with small numbers of subjects note improvement in quality-of-life measures and pain.55,56
In one study of behavioral insomnia therapy for fibromyalgia patients, 8 of 14 participants demonstrated sleep
improvement.57 The effect on pain was modest.
COMPLEMENTARY AND ALTERNATIVE
THERAPIES FOR FIBROMYALGIA
Assessment of complementary and alternative approaches
to fibromyalgia treatment is limited by a paucity of clinical
trials, with the few completed trials sharing the drawbacks
that afflict other fibromyalgia studies.
Meditation-based stress reduction showed benefit in one
study that lacked a control group.58 Dehydroepiandrosterone provided no benefit in pain, fatigue, mood, or functional abilities.59 Melatonin has not been studied in a
blinded fashion.60
Acupuncture is commonly tried by fibromyalgia patients,
but the evidence for acupuncture in fibromyalgia is conflicting. One randomized sham-controlled study demonstrated
no subjective improvement in pain between acupuncture
and sham acupuncture.61 A more recent randomized trial,
however, demonstrated that patients who received acupuncture (vs sham acupuncture) had significantly greater improvements in FIQ scores at 1 and 7 months after treatment.62 An earlier study suggested that electroacupuncture
was more effective than sham therapy for fibromyalgia, but
the study may not have been adequately blinded.63
The alternative therapies purported to treat fibromyalgia
are numerous, unregulated, unstudied, and easily found in
advertisements in lay fibromyalgia publications. Examples
abound in a recent issue of Fibromyalgia Aware magazine.64 An advertisement for infrared therapy, for instance,
makes various claims for relief of pain and stiffness, improved energy, and a better sense of well-being. Another ad
Abeles et al
Table
Fibromyalgia Therapy
559
Drugs with Positive Effects on Fibromyalgia in Randomized Controlled Trials
Drug
Mechanism of Action
Dose
Positive Effect(s) in
Fibromyalgia
Increases synaptic availability 10 mg qhs/25-50 mg qhs Several clinical trials have
demonstrated short-term
of both serotonin and
improvement in pain and
norepinephrine in the
sleep
central nervous system by
decreasing their uptake
10 mg qhs/10 mg qhs-20 One placebo-controlled trial
Cyclobenzaprine Reduces tonic activity of
mg bid
has demonstrated
alpha and gamma motor
improvement in pain and
neurons, leading to muscle
fatigue; subsequent
relaxation; structurally
studies have not shown a
similar to tricyclic
difference between
antidepressants
placebo and
cyclobenzaprine
treatment
2 RCTs have demonstrated
Fluoxetine
Inhibits reuptake of serotonin 20 mg qd/20-80 mg qd
short-term improvement
in the central nervous
in sleep and pain (the
system, increasing its
latter at ⬎20 mg/day)
synaptic availability
2 RCTs have demonstrated
Duloxetine
Inhibits reuptake of serotonin 30 mg qd/60 mg qd-60
mg bid
short-term improvement
and norepinephrine in the
in pain and most
central nervous system
secondary outcome
central nervous system;
fibromyalgia measures
weak inhibitor of central
nervous system dopamine
reuptake
Milnacipran
Inhibits reuptake of serotonin 25 mg qd/100 mg bid
One RCT showed significant
and norepinephrine in the
improvement in pain and
central nervous system
secondary outcome
measures
Tramadol
Blocks ascending pain
50 mg/50 mg tid-100 mg One of 2 RCTs has shown
pathways by weakly binding
tid
very modest short-term
to ␮-opiate receptors in
improvement in pain
the central nervous system;
weak reuptake inhibitor of
norepinephrine and
serotonin in the central
nervous system
Pregabalin
In the central nervous
50 mg tid/100 mg
One RCT showed
system, binds to ␣2-␦
tid-150 mg tid
improvement in pain
only with 450 mg/day;
subunit of voltage-gated
improved sleep quality
calcium channels, thus
and fatigue at ⱖ300 mg/
inhibiting excitatory
day
neurotransmitter release
Amitriptyline
Drawbacks
Has anticholinergic,
antihistaminic, and antiadrenergic side effects
High incidence of side-effects
High incidence of side effects
often lead to drug
discontinuation
Not available in the US
Has abuse potential and may
cause dependence
Cam be used in combination
with any of the above
therapies
Abbreviations: qhs ⫽ at bedtime; bid ⫽ twice a day; qd ⫽ every day; tid ⫽ 3 times a day; RCT ⫽ randomized controlled trial.
promotes a mattress claiming to relieve “the pressure
points” that will allow for “REM sleep.” Yet another advertisement purports a simple solution for the abnormal foot
structure that, the ad claims, perpetuates fibromyalgia pain.
In an advertisement for bottled water, aches, pains, and even
fatigue are apparently magnified by the slightest hint of
dehydration. A brand of moistened towelette claims it has
been “clinically shown to relieve pain associated with fibromyalgia.” While such alternative therapies can range from
sensible to bizarre, none have been adequately validated.
APPROACH TO THE PATIENT WITH
FIBROMYALGIA: PRACTICE-BASED EVIDENCE IN
THE ABSENCE OF EVIDENCE-BASED PRACTICE
Despite a paucity of solid data in support of many fibromyalgia therapies, the physician caring for a fibromyalgia patient is confronted with an individual whose discomfort is
significant, and whose need for melioration is unquestionable. A number of treatments have shown clinical benefit
when compared with placebo (see Table), although fre-
560
quently not in a majority of the patients studied. Indeed, the
heterogeneity of fibromyalgia patients renders a “one-sizefits-all” approach unlikely to be broadly efficacious, and
controlled trials that fail to account for heterogeneity also
might fail to tease out useful effects in subsets of patients.
Additionally, most fibromyalgia patients exhibit multiple
symptoms in addition to pain and tenderness, and therefore
require simultaneous treatment for multiple aspects of their
illness. While the use of combination therapy may offer the
best hope for fibromyalgia management, almost all clinical
trials for fibromyalgia have tested only single therapies.
Clinical experience suggests that particular treatments
work in some patients, sometimes despite failure in clinical
trials. Thus, fibromyalgia treatment choices must be made
on an empiric basis, informed wherever possible by evidence. For most patients, the agent of first choice probably
remains amitriptyline or nortriptyline at bedtime, initiated at
10 mg and increased incrementally as needed to maximum
benefit. If these are not tolerated, low-dose cyclobenzaprine
at bedtime may be initiated; other muscle relaxants also
might be efficacious. A patient who presents with isolated
generalized pain without other associated symptoms may
respond to a simple analgesic such as tramadol. Patients
with depression may particularly benefit from SSRIs or
SNRIs. Patients who fail analgesics, muscle relaxants, or
antidepressants may benefit from the use of pregabalin
or gabapentin. For most of these therapies, patients need
to be reminded that at least several weeks may be required to derive benefit. A failure to respond to one
therapy indicates a need for a trial (or addition) of another agent. Because therapeutic responses are rarely
durable, clinicians should not be disheartened when a
medication loses its initial efficacy. Successful treatment
of fibromyalgia may require regular reassessment and
possible rotation of medications.
Although no particular physical therapies have definitively proven to be of benefit in fibromyalgia, we encourage
all our fibromyalgia patients to participate in some form of
low-impact exercise, such as aquatherapy. Patients need to
be reminded to not be discouraged by limited exercise
capacity at the outset. Moreover, fibromyalgia patients
should be encouraged to increase their exercise very gradually; an overly aggressive regimen may lead to significant
postexercise discomfort and future noncompliance.
Finally, it is of paramount importance to provide fibromyalgia patients with education, emotional support, and
reassurance. Patients should be reassured that, despite the
severity of their pain, fibromyalgia is an otherwise benign
condition that does not lead to bodily damage or death. The
treating physician needs to acknowledge the patient’s experience of pain, because fibromyalgia patients frequently
have had their symptoms ignored or dismissed. The challenge is to produce a compassionate and comprehensive
treatment program for all aspects of the fibromyalgia patient’s illness.
The American Journal of Medicine, Vol 121, No 7, July 2008
References
1. Abeles AM, Pillinger MH, Solitar BM, Abeles M. Narrative review:
the pathophysiology of fibromyalgia. Ann Intern Med. 2007;146(10):
726-734.
2. Galea C, Lim A, Reisine S, et al. Self reported medication and
perceived efficacy of treatment among a sample of fibromylagia patients. Arthritis Rheum. 2003;48(Suppl):S711.
3. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA. 2004;292(19):2388-2395.
4. Leventhal LJ. Management of fibromyalgia. Ann Intern Med. 1999;
131(11):850-858.
5. Wolfe F, Anderson J, Harkness D, et al. Health status and disease
severity in fibromyalgia: results of a six-center longitudinal study.
Arthritis Rheum. 1997;40(9):1571-1579.
6. Leventhal L. Management of fibromyalgia. Ann Intern Med. 2000;
132(12):1005.
7. MacFarlane GJ, Thomas E, Papageorgiou AC, Schollum J, Croft PR,
Silman AJ. The natural history of chronic pain in the community: a
better prognosis than in the clinic? J Rheumatol. 1996;23(9):16171620.
8. Turk DC, Okifuji A, Sinclair JD, Starz TW. Differential responses by
psychosocial subgroups of fibromyalgia syndrome patients to an interdisciplinary treatment. Arthritis Care Res. 1998;11(5):397-404.
9. Thieme K, Turk DC. Heterogeneity of psychophysiological stress
responses in fibromyalgia syndrome patients. Arthritis Res Ther. 2005;
8(1):R9.
10. Finset A, Wigers SH, Gotestam KG. Depressed mood impedes pain
treatment response in patients with fibromyalgia. J Rheumatol. 2004;
31(5):976-980.
11. Thorsen K. Fibromyalgia and cognitive function. Fibromyalgia Network. 2004;10-11.
12. Mease PJ, Clauw DJ, Arnold LM, et al. Fibromyalgia syndrome.
J Rheumatol. 2005;32(11):2270-2277.
13. Carette S, McCain GA, Bell DA, Fam AG. Evaluation of amitriptyline
in primary fibrositis. A double-blind, placebo-controlled study. Arthritis Rheum. 1986;29(5):655-659.
14. Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled
trial of amitriptyline and naproxen in the treatment of patients with
fibromyalgia. Arthritis Rheum. 1986;29(11):1371-1377.
15. Scudds RA, McCain GA, Rollman GB, Harth M. Improvements in
pain responsiveness in patients with fibrositis after successful treatment with amitriptyline. J Rheumatol Suppl. 1989;19:98-103.
16. Jaeschke R, Adachi J, Guyatt G, et al. Clinical usefulness of amitriptyline in fibromyalgia: the results of 23 N-of-1 randomized controlled
trials. J Rheumatol. 1991;18(3):447-451.
17. Carette S, Bell MJ, Reynolds WJ, et al. Comparison of amitriptyline,
cyclobenzaprine, and placebo in the treatment of fibromyalgia. A
randomized, double-blind clinical trial. Arthritis Rheum. 1994;37(1):
32-40.
18. Heymann RE, Helfenstein M, Feldman D. A double-blind, randomized, controlled study of amitriptyline, nortriptyline and placebo in
patients with fibromyalgia. An analysis of outcome measures. Clin Exp
Rheumatol. 2001;19(6):697-702.
19. Share NN, McFarlane CS. Cyclobenzaprine: a novel centrally acting
skeletal muscle relaxant. Neuropharmacology. 1975;14(9):675-684.
20. Bennett RM, Gatter RA, Campbell SM, et al. A comparison of cyclobenzaprine and placebo in the management of fibrositis. A doubleblind controlled study. Arthritis Rheum. 1988;31(12):1535-1542.
21. Gatter RA. Pharmacotherapeutics in fibrositis. Am J Med. 1986;
81(3A):63-66.
22. Quimby LG, Gratwick GM, Whitney CD, Block SR. A randomized
trial of cyclobenzaprine for the treatment of fibromyalgia. J Rheumatol
Suppl. 1989;19:140-143.
23. Reynolds WJ, Moldofsky H, Saskin P, Lue FA. The effects of cyclobenzaprine on sleep physiology and symptoms in patients with fibromyalgia. J Rheumatol. 1991;18(3):452-454.
Abeles et al
Fibromyalgia Therapy
24. Tofferi JK, Jackson JL, O’Malley PG. Treatment of fibromyalgia with
cyclobenzaprine: a meta-analysis. Arthritis Rheum. 2004;51(1):9-13.
25. Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo controlled
trial of fluoxetine in fibromyalgia. Scand J Rheumatol. 1994;23(5):
255-259.
26. Goldenberg D, Mayskiy M, Mossey C, et al. A randomized, doubleblind crossover trial of fluoxetine and amitriptyline in the treatment of
fibromyalgia. Arthritis Rheum. 1996;39(11):1852-1859.
27. Arnold LM, Hess EV, Hudson JI, et al. A randomized, placebocontrolled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112(3):191-197.
28. Ozerbil O, Okudan N, Gokbel H, Levendoglu F. Comparison of the
effects of two antidepressants on exercise performance of the female
patients with fibromyalgia. Clin Rheumatol. 2006;25(4):495-497.
29. Anderberg UM, Marteinsdottir I, von Knorring L. Citalopram in patients with fibromyalgia—a randomized, double-blind, placebocontrolled study. Eur J Pain. 2000;4(1):27-35.
30. Patkar AA, Masand PS, Krulewicz S, et al. A randomized, controlled,
trial of controlled release paroxetine in fibromyalgia. Am J Med.
2007;120(5):448-454.
31. 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(9):2974-2984.
32. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran
in patients with fibromyalgia. J Rheumatol. 2005;32(10):1975-1985.
33. Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the
treatment of fibromyalgia syndrome: results of a randomized, doubleblind, placebo-controlled trial. Arthritis Rheum. 2005;52(4):12641273.
34. Crofford LJ, Simpson S, Young JP, et al. A six-month, double-blind,
placebo-controlled, durability of effect study of pregabalin for pain
associated with fibromyalgia. Arthritis Rheum. 2006;54:4118.
35. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the
treatment of fibromyalgia: a randomized, double-blind, placebocontrolled, multicenter trial. Arthritis Rheum. 2007;56(4):1336-1344.
36. Yunus MB, Masi AT, Aldag JC. Short term effects of ibuprofen in
primary fibromyalgia syndrome: a double blind, placebo controlled
trial. J Rheumatol. 1989;16(4):527-532.
37. Clark S, Tindall E, Bennett RM. A double blind crossover trial of
prednisone versus placebo in the treatment of fibrositis. J Rheumatol.
1985;12(5):980-983.
38. 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(7):537-545.
39. Farrar JT, Young JP, Jr, LaMoreaux L, et al. Clinical importance of
changes in chronic pain intensity measured on an 11-point numerical
pain rating scale. Pain. 2001;94(2):149-158.
40. Bennett RM, Schein J, Kosinski MR, et al. Impact of fibromyalgia pain
on health-related quality of life before and after treatment with tramadol/acetaminophen. Arthritis Rheum. 2005;53(4):519-527.
41. Bennett R, Degarmo P, Clark S. A one year double blind placebo
controlled study of guaifenesin in fibromyalgia. Arthritis Rheum.
1996;39:S212.
42. Russell IJ, Fletcher EM, Michalek JE, et al. Treatment of primary
fibrositis/fibromyalgia syndrome with ibuprofen and alprazolam. A
double-blind, placebo-controlled study. Arthritis Rheum. 1991;34(5):
552-560.
43. Moldofsky H, Lue F, Mously C, et al. The effect of zolpidem in
fibromyalgia: a dose-ranging, double-blind, placebo-controlled modified crossover study. J Rheumatol. 1997;24:1012-1013.
561
44. Russell IJ, Michalek JE, Flechas JD, Abraham GE. Treatment of
fibromyalgia syndrome with Super Malic: a randomized, double blind,
placebo controlled, crossover pilot study. J Rheumatol. 1995;22(5):
953-958.
45. Bibolotti E, Borghi C, Paculli E. The management of fibrositis: a
double-blind comparison of maprotiline, chlorimipramine, and placebo. Clin Trials J. 1986;23:269-280.
46. Karjalainen K, Malmivaara A, van Tulder M, et al. Multidisciplinary
rehabilitation for fibromyalgia and musculoskeletal pain in working
age adults. Cochrane Database Syst Rev. 2000(2):CD001984.
47. Sim J, Adams N. Systematic review of randomized controlled trials of
nonpharmacological interventions for fibromyalgia. Clin J Pain. 2002;
18(5):324-336.
48. Mengshoel AM, Vollestad NK, Forre O. Pain and fatigue induced by
exercise in fibromyalgia patients and sedentary healthy subjects. Clin
Exp Rheumatol. 1995;13(4):477-482.
49. Moldofsky H, Scarisbrick P, England R, Smythe H. Musculosketal
symptoms and non-REM sleep disturbance in patients with “fibrositis
syndrome” and healthy subjects. Psychosom Med. 1975;37(4):341351.
50. Bennett RM. Physical fitness and muscle metabolism in the fibromyalgia syndrome: an overview. J Rheumatol Suppl. 1989;19:28-29.
51. McCain GA, Bell DA, Mai FM, Halliday PD. A controlled study of the
effects of a supervised cardiovascular fitness training program on the
manifestations of primary fibromyalgia. Arthritis Rheum. 1988;31(9):
1135-1141.
52. Burckhardt CS, Mannerkorpi K, Hedenberg L, Bjelle A. A randomized, controlled clinical trial of education and physical training for
women with fibromyalgia. J Rheumatol. 1994;21(4):714-720.
53. Martin L, Nutting A, MacIntosh BR, et al. An exercise program in the
treatment of fibromyalgia. J Rheumatol. 1996;23(6):1050-1053.
54. Staud R, Robinson ME, Price DD. Isometric exercise has opposite
effects on central pain mechanisms in fibromyalgia patients compared
to normal controls. Pain. 2005;118(1-2):176-184.
55. Gusi N, Tomas-Carus P, Hakkinen A, et al. Exercise in waist-high
warm water decreases pain and improves health-related quality of life
and strength in the lower extremities in women with fibromyalgia.
Arthritis Rheum. 2006;55(1):66-73.
56. Assis MR, Silva LE, Alves AM, et al. A randomized controlled trial of
deep water running: clinical effectiveness of aquatic exercise to treat
fibromyalgia. Arthritis Rheum. 2006;55(1):57-65.
57. Edinger JD, Wohlgemuth WK, Krystal AD, Rice JR. Behavioral insomnia therapy for fibromyalgia patients: a randomized clinical trial.
Arch Intern Med. 2005;165(21):2527-2535.
58. Kaplan KH, Goldenberg DL, Galvin-Nadeau M. The impact of a
meditation-based stress reduction program on fibromyalgia. Gen Hosp
Psychiatry. 1993;15(5):284-289.
59. Finckh A, Berner IC, Aubry-Rozier B, So AK. A randomized controlled trial of dehydroepiandrosterone in postmenopausal women with
fibromyalgia. J Rheumatol. 2005;32(7):1336-1340.
60. Citera G, Arias MA, Maldonado-Cocco JA, et al. The effect of melatonin in patients with fibromyalgia: a pilot study. Clin Rheumatol.
2000;19(1):9-13.
61. Assefi NP, Sherman KJ, Jacobsen C, et al. A randomized clinical trial
of acupuncture compared with sham acupuncture in fibromyalgia. Ann
Intern Med. 2005;143(1):10-19.
62. Martin DP, Sletten CD, Williams BA, Berger IH. Improvement in
fibromyalgia symptoms with acupuncture: results of a randomized
controlled trial. Mayo Clin Proc. 2006;81(6):749-757.
63. Deluze C, Bosia L, Zirbs A, et al. Electroacupuncture in fibromyalgia:
results of a controlled trial. BMJ. 1992;305(6864):1249-1252.
64. Fibromyalgia Awareness, vol. 8. Dec. 2004-March 2005.