reviews

a symptom-based approach to pharmacologic

management of fibromyalgia
Chad S. Boomershine and Leslie J. Crofford
abstract | Fibromyalgia is a prevalent disorder that is characterized by widespread pain along with numerous
other symptoms, including fatigue, poor sleep, mood disorders, and stiffness. Previous guidelines for the
management of fibromyalgia recommended an approach that integrates pharmacologic and nonpharmacologic
therapies selected according to the symptoms experienced by individual patients. However, they offered
no recommendations for a system of patient assessment that would provide a basis for individualized
treatment selection. we present a simple, rapid and easily remembered system for symptom quantitation
and pharmacologic management of fibromyalgia that combines visual analogue scale symptom scores from a
modified form of the disease-neutral Fibromyalgia impact Questionnaire, with a review of medications that can
be used to treat the individual symptoms. This symptom-based approach is amenable to caring for patients
with fibromyalgia in a busy clinical practice.

Boomershine, C. s. & Crofford, L. J. Nat. Rev. Rheumatol. 5, 191–199 (2009); doi:10.1038/nrrheum.2009.25

Introduction
Fibromyalgia is of particular importance to rheumatolo­
gists. Between 10% and 20% of new patients presenting
to rheumatology clinics are afflicted with the disorder,
which disproportionately affects the type of patients
commonly cared for by rheumatologists, including
women, the elderly and patients with inflammatory
autoimmune conditions.1 in fact, 20% of patients with
rheumatoid arthritis (ra) and 50% of patients with sys­
temic lupus erythematosus suffer from fibromyalgia,
and the presence of this disorder has a detrimental effect
on disease outcomes for inflammatory disorders.2,3 as
rheumatologists often manage fibromyalgia that is secon­
dary to a primary inflammatory rheumatic condition,
the high prevalence of fibromyalgia, coupled with short­
ages in the rheumatology workforce, creates difficulty in
managing high volumes of referrals in many practices.
the specific exclusion of patients with fibromyalgia from
rheumatology practices is sometimes justified by com­
monly held misconceptions about the disease. one such
misconception is that fibromyalgia patients require too
much time and cannot be effectively managed in a busy
clinical practice. Furthermore, despite the availability of
effective treatments for managing its symptoms, many
rheumatologists have had little success in treating fibro­
myalgia, which has led some to wrongly conclude that it
cannot be successfully managed. other rheumatologists
refuse to treat patients with fibromyalgia because of
Competing interests
Cs Boomershine has declared associations with the following
companies: Cypress Bioscience, eli Lilly and Company, Forest
Pharmaceuticals and Pfizer. LJ Crofford has declared
associations with the following companies: Allergan, Boehringer
ingelheim, Pfizer and wyeth. see the article online for full details
of the relationships.
controversy over the existence of fibromyalgia as a
discrete disease entity.4
we believe that the care of patients with fibromyalgia
can be improved by using a symptom­based approach.
as the effective management of fibromyalgia requires
the identification and treatment of individual symp­
toms,5 a symptom­based management scheme would
limit treatment failures that could arise from an exclusive
focus on pain—a by­product of the american College of
rheumatology (aCr) fibromyalgia classification criteria,
which are centered around widespread pain to the exclu­
sion of other common symptoms.6 a symptom­based
approach is hampered, however, by the inability of many
patients to effectively articulate their symptom burden,
and the inability of clinicians to interpret the patient’s
complaints into a coherent, intellectual framework
from which to make treatment decisions. Furthermore,
although self­report questionnaires that quantify
symptom severity exist, their length and complexity
preclude their use in busy clinical practice settings.
Symptom quantitation
the Fibromyalgia impact Questionnaire (FiQ) is the most
widely used measure for quantifying global fibromyalgia vanderbilt University,
disease severity; it includes a combination of 11 questions Nashville, TN, UsA
(CS Boomershine).
on difficulty with activities of daily living (aDl), 2 day­ University of Kentucky,
of­the­week questions that ask “how many days in the Lexington, KY, UsA
(lJ Crofford).
past week did you feel good?” and “how many days did
you miss work, including housework, because of fibro­ Correspondence:
myalgia?” and 7 visual analogue scale (vas) questions Cs Boomershine,
T3219 MCN,
that assess the severity of work difficulty, pain, fatigue, 1161 21st Ave south,
sleep quality, stiffness, anxiety and depression caused Nashville,
TN 37232–2681, UsA
by fibromyalgia that can be used to direct decisions on chad.boomershine@
patient care.7 the aDl questions have been criticized, vanderbilt.edu

nature reviews | rheumatology volume 5 | aPril 2009 | 191

© 2009 Macmillan Publishers Limited. All rights reserved

 reviews
Key points
■ effective treatment of fibromyalgia requires the management of all clinically
relevant symptoms, using an individualized, integrative approach that combines
pharmacologic and nonpharmacologic modalities
■ Pregabalin, duloxetine and milnacipran are the only FDA-approved medications
for the management of fibromyalgia
■ Additional pharmacologic treatment should focus on symptoms of fatigue,
insomnia (sleep quality), blues (depression and anxiety), rigidity (stiffness)
and ‘ow!’ (pain and work interference), recalled using the mnemonic ‘FiBrO’
■ The modified visual analogue scale of the Fibromyalgia impact Questionnaire
can be used to individualize pharmacologic therapy and monitor treatment
response for FiBrO symptoms
■ symptoms of fatigue, poor sleep, mood disorders, stiffness and pain can be
treated with stimulants, sleep aids, antidepressants, muscle relaxants, and
analgesics, respectively
■ The use of narcotics and benzodiazepines should be avoided when treating
patients with fibromyalgia; steroids and NsAiDs should only be used to treat
underlying inflammatory conditions if present
however, both for their gender bias and on psychometric
grounds,8,9 and the length and scoring complexity of the
aDl and day­of­the­week questions make the FiQ dif­
ficult to use in routine clinical care. also, patients are
often unable to dissect the specific contribution fibro­
myalgia makes to their disability, and physicians uneasy
with the concept of this disorder might refuse to admini­
ster the FiQ owing to the speci fic reference to fibro­
myalgia. Fortunately, the vas of the FiQ can be modified
to become disease­neutral, and can be combined with
each other to produce a global disease severity score
that correlates highly with the full FiQ global score.10 in
addition, vas scores can be used individually to quan­
tify the severity of individual fibromyalgia symptoms
(Figure 1).10 a modified vas of the FiQ (mvasFiQ)
provides a rapid, individualized assessment of symptom
burden that can provide the basis for initial pharmaco­
logic choices and can also be used to monitor therapeutic
response over time. the mvasFiQ measure is ideally
suited to directing patient management in clinical prac­
tice, as it can be administered in paper form, or can be
easily recalled (using the FiBro mnemonic discussed
below) for verbal use.
Pharmacologic management of symptoms
Four general points should be kept in mind when con­
sidering pharmacologic treatments for patients with
fibromyalgia. First, primary disorders that can mimic
fibromyalgia symptoms—including vitamin deficien­
cies, anemia, or metabolic, psychiatric, oncologic or
inflam matory disorders—should be identified and
treated before symptom­specific therapies are initiated.
a comprehensive history should be taken, and physical
and appropriate laboratory examination done includ­
ing, but not limited to, CBC, metabolic panel, erythro­
cyte sedimentation rate, C­reactive protein and thyroid
function studies (Figure 2). Fibromyalgia, however,
frequently coexists with other diseases, and those patients
192 | APRIL 2009 | voLume 5
© 2009 Macmillan Publishers Limited. All rights reserved
who remain symptomatic despite adequate treatment of
their primary disorder should be treated for fibromyalgia.
second, while a discussion of fibromyalgia diagnosis is
beyond the scope of this article, the aCr classification
criteria were not intended for clinical use: reliance on cri­
teria fulfillment for diagnosis misses 46% of fibromyalgia
patients.11 a clinical diagnosis must, therefore, be made,
and this review is intended to apply to all patients who
are clinically diagnosed, irrespective of whether they meet
the aCr criteria. third, as over half of patients with fibro­
myalgia have multiple medication intolerances,12 treat­
ments should be started individually at low doses that
are slowly increased and/or combined with other medi­
cations; furthermore, multiple medications or combina­
tions might need to be tried before a regimen is found that
the patient will tolerate. Finally, even though this review
focuses on pharmacologic treatments, medications have
a limited role in fibromyalgia treatment; that role is to
manage symptoms so that patients can, in the long­term,
also benefit from non­pharmacologic therapies, including
exercise, education and behavioral therapies (Figure 2).5
approved medications
as pregabalin, duloxetine and milnacipran are all FDa­
approved for fibromyalgia management, it is reasonable
to consider these as ‘anchor’ drugs, analogous to the
use of methotrexate in ra. all three drugs have shown
similar efficacy in ameliorating pain,13 but their abilities
to manage other fibromyalgia symptoms differ greatly,
which, along with their different pharmacodynamic
and safety profiles, often make one a better initial choice
than the others for an individual patient. Pregabalin is
an α2δ calcium­channel antagonist that acts by limiting
the neuronal release of excitatory neurotransmitters.
Pregabalin has shown a capability to decrease sleep
latency and modify sleep architecture by improving
slow­wave sleep, making it a particularly good choice for
fibromyalgia patients with sleep complaints.14 Pregabalin
has multiple possible adverse effects, however, includ­
ing dizziness, somnolence, weight gain and peripheral
edema, the risks of which increase with increasing dose.
whereas the approved dosage is 300–450 mg per day,
divided into two doses, we recommend beginning
pregabalin treatment with a single small dose (25–75 mg)
at dinner or with an evening snack, as food slows the
absorption of the drug and can limit dizziness, and titrat­
ing upwards weekly until the maximal effect is achieved.
many patients respond to once­daily night­time dosing,
but those with severe peripheral neuropathy or allo­
dynia might benefit from twice­daily dosing. Patients on
pregabalin should be monitored closely for worsening
of fatigue. Being an adjunctive antiepileptic medication,
pregabalin should be discontinued gradually, as stopping
administration abruptly could, in theory, precipitate sei­
zures in susceptible patients. Gabapentin, an older drug
with the same mechanism of action, has also been effec­
tive in the treatment of patients with fibromyalgia, and
is discussed below.15
www.nature.com/nrrheum
 reviews

Duloxetine and milnacipran belong to the serotonin–

norepinephrine reuptake inhibitor (snri) class of Questionnaire
antidepressants, which improve symptoms of pain by Directions: Please indicate by marking a “/” through the line at a point that best
increasing the activity of noradrenergic antinociceptive indicates how you felt overall for the past week.
pathways. these drugs should be considered as first­line
agents in fibromyalgia patients with severe symptoms of Fatigue: How tired have you been?
depression (n.B. milnacipran is approved for treating No tiredness |____|____|____|____|____|____|____|____|____|____| Very tired
major depressive disorder in europe and Japan, but it is 0 1 2 3 4 5 6 7 8 9 10
not FDa­approved for treating this disorder in the us).
also, as it has a higher affinity for the norepinephrine Insomnia: How have you felt when you got up in the morning?
transporter than does duloxetine, milnacipran may be Awoke well |____|____|____|____|____|____|____|____|____|____| Awoke very
rested 0 1 2 3 4 5 6 7 8 9 10 tired
better for patients with severe fatigue and/or cognitive
dysfunction (the so­called fibrofog). 16 the indicated
dose of duloxetine is 60 mg once daily, but we recom­ Blues: How depressed or blue have you felt?
Not depressed |____|____|____|____|____|____|____|____|____|____| Very depressed
mend starting with a single dose of 20 mg or 30 mg in 0 1 2 3 4 5 6 7 8 9 10
the morning, with dose increases every 2 weeks to a
maximum dose of 60 mg if necessary. the indicated
How nervous or anxious have you felt?
dose of milnacipran is 100 mg daily, divided into two Not anxious |____|____|____|____|____|____|____|____|____|____| Very anxious
doses, but we recommend starting with a single 12.5 mg 0 1 2 3 4 5 6 7 8 9 10
morning dose and gradually increasing the morning
dose to 50 mg, if needed, before adding an evening dose. Rigidity: How bad has your stiffness been?
Common adverse effects of duloxetine and milnacipran No stiffness |____|____|____|____|____|____|____|____|____|____| Very stiff
0 1 2 3 4 5 6 7 8 9 10
include nausea and decreased appetite, which might
make them a better choice than pregabalin for obese
patients. owing to its hepatic metabolism and potential Ow!: How bad has your pain been?
No pain |____|____|____|____|____|____|____|____|____|____| Very severe
drug–drug interactions, duloxetine should be avoided 0 1 2 3 4 5 6 7 8 9 10 pain
in patients with severe hepatic or renal impairment, and
caution is advised when combining duloxetine with other
When you worked, how much did pain or other symptoms interfere with your
agents. with appropriate dosage adjustments, pregaba­ ability to do your work, including housework?
lin and milnacipran can both be used in patients with No problem |____|____|____|____|____|____|____|____|____|____| Great difficulty
hepatic or renal impairment, and they share properties with work 0 1 2 3 4 5 6 7 8 9 10 with work
that make them safer for use with other agents, including
minimal hepatic metabolism, low capacity for binding to
plasma proteins, and low likelihood of being involved in
clinically relevant pharmacokinetic drug interactions.17,18
as with all serotonin­activating medications, duloxetine
and milnacipran can increase the risk of bleeding and/ Figure 1 | The modified visual analogue scale of the Fibromyalgia impact
or suicidal tendencies, and should be used with caution Questionnaire. The FiBrO mnemonic can be used to remember the items on this
in patients with a history of, or who are at risk for, these questionnaire (mvAsFiQ). vAsFiQ modified with permission from rM Bennett.
conditions. also, duloxetine and milnacipran can both Adapted with permission from The Journal of rheumatology © Burckhardt, C. s.,
Clark, s. r. & Bennett, r. M. The fibromyalgia impact questionnaire: development
affect blood pressure; monitoring is recommended.
and validation. J. Rheumatol. 18, 728–734 (1991).
the important therapeutic property of both duloxe­
tine and milnacipran is reuptake inhibition of norepi­
nephrine and serotonin. this effect can be achieved effective in patients with fibromyalgia.21,22 its use is also
with other medications, although they are not approved discussed below.
specifically for fibromyalgia. For example, reuptake Given the differing therapeutic mechanisms and
inhibition of both norepinephrine and serotonin can adverse effect profiles of α2δ calcium­channel antago­
be accomplished by combining a specific serotonin nists and snris, synergy achieved through a combina­
reuptake inhibitor, such as fluoxetine, which has been tion strategy could benefit patients who fail to respond
shown to be effective in fibromyalgia,19 with an agent to either drug alone. a trial of combination therapy with
that inhibits norepinephrine reuptake, such as traza­ the snri venlafaxine and the α2δ antagonist gabapentin,
done. However, combining multiple serotonin­active for instance, improved symptoms of pain, fatigue, mood
medications risks the development of serotonin syn­ disturbance and insomnia in patients with neuropathic
drome, and patients should be warned and monitored pain who did not respond to gabapentin monotherapy.23
for relevant signs and symptoms.20 although not submit­ the potential for additive adverse effects should be
ted to the FDa for approval in a fibromyalgia indication, borne in mind, however, and randomized, combination
amitriptyline also provides balanced reuptake inhibition trials are needed to confirm the safety and efficacy of
and has been shown in multiple meta­analyses to be such an approach.

nature reviews | rheumatology volume 5 | aPril 2009 | 193

© 2009 Macmillan Publishers Limited. All rights reserved

 reviews

Patient evaluation
Does the patient have diffuse widespread pain
(bilateral, above and below the waist including the axial spine)?

Yes No

Physical examination, differential diagnosis, and laboratory evaluation Consider alternative diagnosis
Does the patient have another condition that could explain their pain?

Yes No

Persistent Treat fibromyalgia symptoms and individualize therapy using the mVASFIQ
Treat and re-evaluate
symptoms Administer mVASFIQ to all patients and use answers to individualize therapy

Treat fibromyalgia symptoms: all patients get ‘PAIN’

Pregabalin,a duloxetinea or milnaciprana: pregabalin (25–75 mg at night) if high insomnia score, duloxetine (20–30 mg in morning) if high
depression score or milnacipran (12.5 mg in morning) if high fatigue score
Activity: daily stretching, both low-impact aerobic and resistance exercise alternating every other day
Information: discuss fibromyalgia, provide information (e.g. http://www.knowfibro.com) and support group sources (e.g.
http://www.fmaware.org/site/PageServer?pagename=community_supportGroupDirectory)
No narcotics: avoid narcotics, benzodiazepines and steroids

Individualize symptom-based therapy using the mVASFIQ to treat ‘FIBRO’

Re-evaluate patients using the mVASFIQ at each visit to monitor therapy

Fatigue (physical and/or Insomnia (insomnia and/or
mental) nonrestorative sleep)
■ Modafinil (50–100 mg) ■ Sleep hygiene
or methylphenidate recommendations and
(5–10 mg) on screening for OSA and RLS
awakening with a ■ Treat insomnia with
second dose at lunch eszopiclone (1–3 mg),
if necessary ramelteon (8 mg) or a
■ Consider switching to sedating anti-depressant
sustained-release at night
formulations if patient ■ Treat RLS with dopamine
tolerates immediate agonists at night
release medications ■ Sleep study for OSA
■ Nonrestorative sleep
treated with pregabalina
(25–75 mg) at night
Blues (depression Rigidity (stiffness) Ow! (pain)
and/or anxiety) ■ Cyclobenzaprine ■ Pregabalin,a duloxetine,a
■ Psychiatric or (10–50 mg) or or milnaciprana at
psychologic referral tizanidine (4–36 mg) indicated doses
■ Antidepressant divided over the day ■ Paracetamol (1,000 mg
medications—SNRI starting at night four times daily) or
preferred, such as ■ Can add tramadol tramadol–paracetamol
duloxetine (60 mg –paracetamol (37.5 mg/325 mg up to
once in morning), (37.5 mg/325 mg) up four times daily)
milnacipran (50 mg to four times daily if ■ Gabapentin (100–300 mg
twice daily), needed each night to start,
venlafaxine (37.5 mg ■ Can substitute increased to 1,200–
twice daily); older methocarbamol or 2,400 mg divided three
SSRIs and/or TCAs metaxalone if times daily) can be tried
optional with TCAs cyclobenzaprine or as an alternative to
given at night tizanidine too sedating pregabalin

Figure 2 | Proposed algorithm for the symptom-based management of fibromyalgia in clinical practice. Patients with
fibromyalgia are identified and then assessed with the mvAsFiQ. The first-line treatment incorporates drugs specifically
indicated for fibromyalgia, as well as nonpharmacologic measures. Treatment is customized by use of the mvAsFiQ.
Patients should be reassessed with the mvAsFiQ at each visit, with treatment modified as required, as adverse effects of
medications for one symptom can worsen others. aOnly pregabalin, duloxetine and milnacipran are approved by the FDA for
management of fibromyalgia. Abbreviations: mvAsFiQ, modified visual analogue scale of the Fibromyalgia impact
Questionnaire; OsA, obstructive sleep apnea; rLs, restless legs syndrome; sNri, serotonin–norepinephrine reuptake
inhibitor; ssri, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Symptom management by the FIBro method
Patients with fibromyalgia often fail to respond ade­
quately to a single ‘anchor’ medication. Patients might
have a response for one symptom (typically pain) but lack
responses in other associated fibromyalgia symptoms,
or some symptoms might worsen while others improve.
owing to the heterogeneity and complexity of symp­
toms experienced by individual fibromyalgia patients,
a brief, comprehensive assessment tool suitable for use
in busy clinics was needed. the FiBro mnemonic was
developed as a memory aid to recall key fibromyalgia
symptoms, and the mvasFiQ questions were used to
assess them (Figure 1). the letter ‘F’ indicates fatigue,
‘i’ insomnia (sleep quality), ‘B’ blues (including depres­
sion and anxiety), ‘r’ rigidity (stiffness), and ‘o’ ‘ow!’
(pain and work disability). mvasFiQ questions can be
administered as printed forms, or patients can be queried
verbally with answers rated on a 0–10 numeric scale. the
mvasFiQ scores can be summed to provide a global
disease severity measure and can also be considered

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individually to assess the severity of individual symp­
toms.10 By administering the mvasFiQ at baseline and
follow­up visits, the patient’s response to therapy can be
monitored and treatments can be individualized. as pre­
viously stated, we recommend a ‘start low and go slow’
approach to fibromyalgia management, beginning with
a single medication at a low dose and gradually titrating
before adding additional medications. Drug combina­
tions should be chosen carefully in order to limit the risk
of drug–drug interactions, and patients should be moni­
tored closely for signs or symptoms of toxic effects. the
following sections will expand the information presented
in Figure 2 and describe medications used to manage
each FiBro symptom.
Fatigue (stimulants)
many patients with fibromyalgia experience debilitating
symptoms of fatigue, which manifest physically as severe
exhaustion and mentally as difficulties in memory and
attention (termed ‘fibrofog’). the long­term manage­
ment of fatigue should rely on improving physical
fitness through regular physical activity, but stimulants
can improve the ability of patients to participate in
such therapy and to manage their aDls. modafinil is a
wakefulness­promoting agent that is pharmacologically
distinct from other stimulants and is currently FDa­
approved for the treatment of somnolence associated
with obstructive sleep apnea, narcolepsy and shift­work
syndrome.24 modafinil has been shown to be effective
in improving fatigue associated with multiple disorders,
and three published reports indicate that it possibly has
a benefit in treating fibromyalgia­associated fatigue.25–27
in these studies, effective doses were in the 50–400 mg
range, given primarily as a single morning dose but with
a second, smaller dose added at noon if fatigue symp­
toms returned late in the day. modafinil affects multiple
cytochrome P450 isoenzymes and has the potential to
interact with numerous drug classes. maximum doses
should be lower in the elderly and in patients with
hepatic or renal disease. although modafinil is structu­
rally distinct from other stimulants, its adverse effect
profile is similar; patients with insomnia, hypertension
and anxiety disorders should be closely monitored for
worsening of their signs and symptoms.25 it is impor­
tant to note that stimulants have addiction potential,
and caution is urged when using these agents in patients
with a history of drug abuse. in fact, we would discourage
the use of these medications in patients with a history of
addiction to alcohol or drugs.
although methylphenidate has not been specifically
studied as a treatment for fibromyalgia, it is the most
commonly used stimulant in fibromyalgia therapy, owing
to its low cost and the lack of insurance restrictions on its
use. Psychostimulants could potentially be very helpful
in fibromyalgia patients with ‘fibrofog’, as it can be con­
sidered analogous to adult attention deficit/hyperactivity
disorder and treated similarly.28 excellent reviews of the
diagnosis of adult attention deficit/hyperactivity disorder
nature reviews | rheumatology
© 2009 Macmillan Publishers Limited. All rights reserved
reviews
and its management with stimulant therapies—including
methylphenidate, dexmethylphenidate, amphetamine
salts and atomoxetine—have been published else­
where. 29,30 a thorough discussion of these agents is,
therefore, not included here. However, if the practitio­
ner elects to prescribe psychostimulants, we recommend
a ‘start low and go slow’ approach, using a small dose
of short­acting stimulant given upon awakening and an
additional dose added at noon if necessary, before con­
sidering extended­release formulations once daily. also,
given the relatively high prevalence of bipolar disorder in
patients with fibromyalgia symptoms,31 close monitoring
for the development of mania should be maintained in
stimulant­treated patients.
Insomnia (sleep aids)
improving sleep quality is a vital aspect of disease
management for the majority of patients with fibro­
myalgia. over 90% of fibromyalgia patients complain of
sleep problems, and sleep disruption has been implicated
in the pathogenesis of the disease.32,33 all fibromyalgia
patients should be screened for the presence of under­
lying sleep disorders before symptom­specific pharmaco­
logic therapies are prescribed. Patients at high risk of
obstructive sleep apnea–hypopnea syndrome should be
referred for formal sleep evaluation.34 relevant patients
fulfill at least two of three Berlin Questionnaire criteria,
including persistent snoring, daytime somnolence or
the presence of hypertension or obesity. as one­third
of patients with fibromyalgia also have restless legs syn­
drome (rls),35 all patients should be screened for this
disorder with the four­question international rls study
Group criteria.36 Patients with primary rls should be
treated with a dopamine agonist to determine whether
resolving rls improves their sleep before other sleep
medications are used. two dopamine agonists, prami­
pexole and ropinirole, have been approved by the FDa
for the treatment of rls, and both have been demon­
strated to be efficacious in managing fibromyalgia symp­
toms.37,38 Dopamine agonists are started at a low dose
(0.125 mg per day for pramipexole and 0.25 mg per day
for ropinirole) 2 h before bedtime and gradually increased
in weekly intervals until symptoms of rls have resolved
or patients become intole rant of the treatment. 39,40
although the recommended maximum daily doses for
rls treatment are 0.5 mg for pramipexole and 4 mg
for ropinirole, higher doses have frequently been used
to improve fibromyalgia symptoms, with a mean dose
of 4.5 mg for pramipexole and 6 mg for ropinirole.37,38
owing to the high cost of pramipexole and ropinirole, we
have used generic carbidopa–levodopa (25 mg/100 mg)
combination tablets, which have successfully treated
rls in patients with fibromyalgia (Cs Boomershine and
lJ Crofford, unpublished data).
in patients with fibromyalgia who have difficulty falling
asleep and who fail to respond to psychological and behavi­
oral treatment modalities, FDa­approved pharmacologic
therapies for insomnia should be considered.41 although
volume 5 | aPril 2009 | 195
 reviews
benzodiazepines have long been the mainstay of insom­
nia therapy, we avoid their use in fibromyalgia patients
because of their detrimental effects on sleep architecture,
cognition and their addiction potential. 42 ramelteon
and eszopiclone are the only nonbenzodiazepine, FDa­
approved therapies for insomnia. ramelteon is a selec­
tive melatonin­receptor agonist that is administered as
a single, 8 mg tablet 30 min before bedtime. eszopiclone
is a hypnotic agent given as a 1 mg, 2 mg or 3 mg tablet
immediately before bedtime. the administration of
ramelteon or eszopiclone with high­fat meals should be
avoided, as this slows the absorption of these drugs and
decreases their efficacy. as with all sedatives, patients
using these agents should be closely monitored for
worsening depression or suicidal ideation, and concomi­
tant use of other sedatives should be avoided. adverse
effects of ramelteon are uncommon, but eszopiclone can
cause headache and an unpleasant taste, which can limit
its use. sedating antidepressants can also be beneficial
for improving symptoms of insomnia in the one­third of
fibromyalgia patients with severe depressive symptoms,
and are discussed below.
whereas some fibromyalgia patients experience
insomnia, many sleep for 12 h or more without feeling
refreshed upon awakening. this phenomenon of non­
restorative sleep requires management with medications
that improve sleep quality as opposed to sleep quan­
tity.43 Pregabalin is the recommended first­line agent,
as it improves sleep architecture at recommended doses
and is approved by the FDa for fibromyalgia manage­
ment.14 However, improvements in sleep restoration are
often transient, which renders pregabalin a poor long­
term choice for many patients. Chlorpromazine 100 mg
at bedtime can increase slow­wave sleep and improve
symptoms of pain and mood in fibromyalgia patients,44
but poor tolerance has limited its clinical use. Quetiapine,
an atypical antipsychotic agent, improves sleep architec­
ture45 through effects on sleep quality and numerous
other fibromyalgia symptoms at doses of between 25 mg
and 100 mg per day.46 while generally well tolerated,
quetiapine doses of 100 mg per day have been associ­
ated with increased periodic limb movements; thus, the
lowest effective dose should be used. sodium oxybate, the
commercial form of a naturally occurring neurochemical
approved for cataplexy management, improves sleep and
other fibromyalgia symptoms given as two divided doses
of 3 mg at bedtime and 4 h later.47 this drug is, however,
tightly regulated owing to its substantial abuse poten­
tial, and routine clinical use cannot be recommended
at this time.
Blues (antidepressants and anxiolytics)
the identification and treatment of mood disorders is
crucial in the management of fibromyalgia, as one­third
of patients complain of major problems with depression
and/or anxiety that can severely hamper disease manage­
ment and notably increase suicidality.48,49 as duloxetine
is approved by the FDa for the treatment of fibromyalgia
196 | APRIL 2009 | voLume 5
© 2009 Macmillan Publishers Limited. All rights reserved
as well as depression and anxiety, it is the recommended
first­line treatment for patients with mood disorders
in the us. although daily doses as high as 120 mg are
often used clinically, doses greater than 60 mg per day
are poorly tolerated and not recommended.50 as mil­
nacipran is an snri approved as an antidepressant in
europe and Japan, and as a fibromyalgia management
option at 50 mg twice daily in the us, it is the recom­
mended first­line agent for depressed fibromyalgia
patients in these regions. in addition, mil nacipran
has a higher specificity for norepinephrine reuptake
inhibition than duloxetine, so it may be more effec­
tive for patients with severe fatigue and/or ‘fibrofog’. 16
venlafaxine is a generic snri that has efficacy in fibro­
myalgia management at a dosage of 75 mg per day, and
is a reasonable alternative for patients who cannot afford
branded snris.51 Caution should be used when discon­
tinuing venlafaxine, however, as rebound depression is
common.52 older selective serotonin reuptake inhibitors,
such as fluoxetine and paroxetine, may be effective in
treating fibromyalgia as they also inhibit norepinephrine
reuptake at high doses (40–80 mg per day), but these
doses are often poorly tolerated.53
sedating antidepressants can be particularly helpful in
managing depressed fibromyalgia patients with insom­
nia. tricyclic antidepressants (tCas), including amitrip­
tyline and the structurally related cyclobenzaprine, have
long been used to treat pain and insomnia at low evening
doses (5–10 mg cyclobenzaprine, 10–50 mg amitrip­
tyline). whereas intolerance to high doses often makes
tCa monotherapy insufficient to manage mood dis­
orders, combining low­dose tCas with fluoxetine 20 mg
per day can synergystically treat fibromyalgia symptoms
with minimal adverse effects.54 mirtazapine increases
serotonergic and noradrenergic neurotransmission via
a novel mechanism that could enable its use in patients
who do not tolerate traditional snris; doses of 15–30 mg
at night have been shown to improve symptoms of pain,
insomnia, fatigue, and depression in patients with fibro­
myalgia.55 somnolence with mirtazapine is inversely
proportional to dose, so patients experiencing excessive
sedation at a dose of 15 mg should increase to 30 mg. as
the most­sedative second­generation antidepressant,
trazo done is best suited for patients with insomnia
refractory to other drugs. although trazodone has not
been studied as a treatment for fibromyalgia, an evening
dose of 100 mg improved sleep architecture in patients
with somatoform pain disorder.56
Rigidity (muscle relaxants)
muscle and joint stiffness is a symptom affecting over
75% of patients with fibromyalgia. 6 the etiology of
these symptoms is unknown, but they probably result
from inactivity and deconditioning combined with
the central nervous system abnormalities that under­
lie fibromyalgia. the management of rigidity should
focus on decreasing symptoms enough to enable
patients to maintain employment and encourage them
www.nature.com/nrrheum

to participate in physical activities that improve range
of motion and fitness, including yoga, tai chi and other
low­impact aerobic activities. Centrally acting muscle
relaxants can be helpful as adjunctive therapy in patients
with substantial stiffness. an excellent review of the use
of muscle relaxants for musculoskeletal conditions has
been published that thoroughly describes risks and
benefits of the class;57 this section will focus on the use
of muscle relaxants in fibromyalgia.
Cyclobenzaprine is the most widely used muscle
relaxant for treating fibromyalgia, and has many proper­
ties that make it particularly well suited for managing
this disorder. Cyclobenzaprine is structurally a tCa,
and thus can improve mood and pain symptoms.
whereas the use of cyclobenzaprine during the day
can cause problematic sedation, it can treat insomnia
when used at night. a meta­analysis of randomized,
placebo­controlled trials showed that cyclobenzaprine
significantly improved global fibromyalgia symptoms,
along with symptoms of pain, sleep, and tender points,
with excellent tolerability.58 Cyclobenzaprine can be
particularly useful in managing fibromyalgia ‘flares’
(acute exacerbations of symptoms); however, doses of
10 mg four or five times daily are often needed, which
are larger than those commonly used to treat back
pain (5–10 mg three times daily). Patients receiving
these higher doses should be monitored for worsening
fatigue, counseled to avoid concomitant use of central
nervous system depressants and monitored for anti­
cholinergic adverse effects (dry mouth, urinary reten­
tion, etc). tizanidine, a muscle relaxant with similar
sedative properties to cyclobenzaprine, should be started
with a 4 mg dose at night and gradually increased to a
maximum dose of 36 mg divided over the day if needed.
along with anticholinergic adverse effects, tizanidine
can cause hepatotoxic effects, and laboratory monitor­
ing is required. methocarbamol and metaxalone are
less­sedating muscle relaxants, but evidence for their
effectiveness in managing fibromyalgia symptoms is
limited. Benzodiazepines should be avoided in fibro­
myalgia patients owing to addiction potential and
worsening of sleep. no evidence supports the use of
antispastic agents (such as baclofen or dantrolene) in
fibromyalgia, but they can be helpful for managing
muscle spasms. tramadol has been shown to substan­
tially improve fibromyalgia­associated stiffness, and will
be discussed in the next section.
‘Ow!’ (analgesics)
Pain has long been considered the defining feature of
fibromyalgia syndrome. while the approved agents
have demonstrated efficacy in relieving fibromyalgia
pain, they often are not sufficient when taken alone.
Paracetamol (acetaminophen) has some efficacy in the
management of pain symptoms in fibromyalgia, but
treatment failures are common as the required dose
is usually near the maximum recommended dose of
4,000 mg/day, and patients are often noncompliant with
nature reviews | rheumatology
© 2009 Macmillan Publishers Limited. All rights reserved
reviews
the required frequency of administration. assuming
patients have normal renal and hepatic function, dosing
with extended­release formulations of 1,000 mg para­
cetamol four times daily can improve compliance in
comparison to the eight doses that are required daily
for patients taking immediate­release 500 mg tablets.
However, patients often fail to respond to treatment with
paracetamol. Furthermore, the majority of fibromyalgia
patients prefer to use nsaiDs.59 although all nsaiDs
have similar analgesic effects, evidence of their efficacy
in fibromyalgia management is lacking. nsaiDs are not
recommended in the absence of a concomitant inflam­
matory condition or osteoarthritis, which often serve as
pain triggers in patients with fibromyalgia.
tramadol, a unique narcotic that combines μ­opioid
agonist–antagonist and snri activities, is effective when
used to manage fibromyalgia.5 one or two tramadol–
paracetamol (37.5 mg/325 mg) combination tablets taken
four times daily can substantially lessen pain, stiffness
and work interference in patients with fibromyalgia.60
Common adverse effects of this treatment are nausea,
pruritis and constipation. the risk of abuse and depen­
dence with tramadol is low, and 97% of such cases occur
in patients with a history of substance abuse.61 traditional
narcotics should be avoided in the treatment of fibro­
myalgia, as their efficacy is poor and weaning patients
off narcotics can be very difficult owing to the rebound
pain phenomenon (analogous to rebound headaches)
that can worsen pain symptoms when patients attempt
to discontinue them.
Gabapentin is an α2δ calcium­channel antagonist,
similar to pregabalin, that has proven efficacy in mul­
tiple neuropathic pain syndromes, including fibro­
myalgia. 15 However, gabapentin has pharmacologic
properties that make it more difficult to achieve an
effective, tolerable dose than with pregabalin. an niH­
sponsored, investigator­initiated trial that showed that
gabapentin was effective in improving pain, sleep, and
global fibromyalgia symptoms attempted to titrate
dosing up to 2,400 mg per day (divided into three
doses),15 but, due to patient intolerance, the mean dose
achieved in the trial was only 1,800 mg per day. Patients
should be started on a single low dose of gabapentin
(100–300 mg) at bedtime, with additional doses at
breakfast and lunch added after 1 week and subsequent
increases made to the evening dose. adverse effects of
gabapentin use are similar to those seen with pregaba­
lin, including somnolence, dizziness, fatigue and weight
gain. as with pregabalin, patients should be slowly
tapered off gabapentin because of a theoretical risk of
precipitating seizures.
Conclusions
multiple meta­analyses show conclusively that improve­
ment in fibromyalgia symptoms can be achieved by
use of numerous pharmacologic and nonpharmaco­
logic treatments.62,63 Following the approval of three
agents for the management of fibromyalgia by the FDa,
volume 5 | aPril 2009 | 197
 reviews

clinicians treating patients with fibromyalgia should Review criteria

develop a framework for the use of these drugs in clini­
cal practice to maximize patient response to therapy.
we have presented a rapid, symptom­based method
for the assessment and pharmacologic management of
fibromyalgia that is suitable for use in busy clinics. our
method focuses on symptom identification and manage­
ment that promotes a holistic, patient­centered view of
disease that can improve care regardless of the patient’s
underlying disorder.
english-language articles in the Medline database were
identified by use of the following search terms, alone and
in combination: “fibromyalgia”, “review”, “treatment”,
“pregabalin”, “insomnia”, “modafinil”, “stimulant”,
“attention”, “atomoxetine”, “dopamine”, “sodium oxybate”,
“methylphenidate”, “lupus”, “rheumatoid”, “suicide”,
“fatigue”, “depression”, “anxiety”, “tizanidine”, “baclofen”,
“dantrolene”, “trazodone”, “amitriptyline” and “meta-
analysis”. No date restrictions were placed on the search.

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