Journalo

ofSymptomssandSigns

2
2013;Volumee2,Numberr4

Exp
pert O
Opinion
n

Curre
ent conc
cepts in
n the tre
eatmentt of fibrromyalg
gia
Mahmoudd Slim, PhD, Fernando Riico-Villademooros, MD, Eleena P. Calandre, MD
Instituto de Neurociencias, Universidad de Graanada, Spain.
Correspondding Author: Prof. Elena P. Calanndre, MD, Instituto de Neurocienccias, Universidad de Granada, Avenida de Madrid 11, 18012 Granadda,
Spain. E-maail: epita@ugr.es.

Abstrac
ct
The treatmeent of fibromyalgiaa involves the use of different kindds of therapeutic modalities. Amonng pharmacologicc treatments, seveeral antidepressants
and pregabaalin, an alfa2delta blocker, are the best studied druggs and have the highest degree off evidence for efficacy. Other druggs that may be ussed
and have att least a positive randomized cliniical trial include sodium
s
oxybate, two 5-HT3 recepptor antagonists and
a pramipexole. As it is not an inflammatory ddisease, NSAIDs are not useful in the long-term m
management of fibbromyalgia, but the combination of tramadol with paracetamol has beeen
shown to bee effective. Non-ppharmacologic theerapies include phhysical and psychhological alternativves. Educating paatients to understtand their diseasee is
helpful whenn combined with other non-pharm
macologic alternattives, but has little efficacy by itself. Exercise, parrticularly aerobic exercise, has beeen
shown to im
mprove pain, deprressed mood andd quality of life. C
Cognitive-behaviooral therapy has bbeen shown to im
mprove depressedd mood and to help
the patient to
t cope with the pain, although it lacks direct efficaacy on pain, fatiggue and sleep dissturbances. Multim
modal treatment, combining pharm
macologic and one or more nonn-pharmacologic aalternatives, is coonsidered to be thhe best approach to treat patients with
w fibromyalgia.

Keywords:: fibromyalgia; ppharmacologic trreatment; exercise; education; psychotherapy; multimodal treaatment.

Received: March 14, 20133; Accepted: May 10, 2013; Puublished: Augusst 10, 2013

Introd
duction
The first description off the fibromyaalgia probablyy goes
back to thhe 18th centuryy when the exxpression musscular
rheumatissm was appliied to painful but nondeforrming
musculoskkeletal disordders to be disttinguished from
m articular rheeumatism. At the beginningg of the 20th ccentury Sir Wiilliam Gowerss used the terrm fibrositis and
already mentioned
m
thatt spontaneous pain was freqquently associaated to sleep disturbances
d
aand fatigue, am
mong

others [1]. T
The term fibrromyalgia waas initially prroposed by Yuunus in 1981 in the first ccontrolled studdy
that describeed the clinicaal characteristtics of patiennts
with fibrositiis as compareed with healthhy matched coontrols [2].
However, it was not unttil 1990 that thhe first diagnoostic criteria ffor fibromyallgia were prroposed by thhe
American Coollege of Rheeumatology (ACR) [3]. A
Although the auuthors of the sttudy acknowleedged the exisstence of sym
mptoms such aas fatigue, moorning stiffnesss,

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Treattment of fib
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sleep dissturbances annd other freqquently assocciated

symptomaatology, they did not find that the diagnnostic
accuracy were improveed by consideering them, annd the
myalgia were ssolely
criteria foor the diagnosis of fibrom
establisheed in relation to pain. To bbe diagnosed of fibromyalgia a patient should have experienced w
widespread paain during at least three monnths and to exxperience tendderness in a m
minimum of eeleven of eigghteen
specific teender points. A new set off diagnostic crriteria
was propoosed, also by the ACR, in 2010 [4]. It suubstitutes the ttender point evaluation
e
by a Widespreadd Pain
Index (W
WPI) and adds a Symptom S
Severity Scalee (SS)
that quanttifies fatigue, waking unreffreshed, and cognic
tive sympptoms and alsoo takes in accoount the presennce of
other som
matic symptom
ms. To date both kind of diaagnostic criteriaa coexist.
The caardinal symptoom that definnes fibromyalggia is
chronic ggeneralized m
musculoskeletaal pain withouut an
underlyinng cause. How
wever, althouggh pain is a prominent featuure of the fibrromyalgia synndrome, other disabling sym
mptoms coexisst with it. Sleeep disturbancees and
chronic fa
fatigue are preesent in almosst all patientss with
fibromyallgia; many pattients also repport cognitive difficulties, m
mood disturbannces, stiffness, balance probblems
and hypeersensitivity too environmenntal stimuli [55]. In
addition, patients withh fibromyalgiaa frequently suffer
s
from a wiide array of asssociated mediical and psychhiatric
conditionss which stronngly contributte to a diminnished
quality off life [6].
Pain inn fibromyalgiaa is not assocciated with innflammation noor is of neuroppathic origin evven if referredd pain,
hyperalgeesia, and evenn allodynia arre not uncom
mmon.
Currentlyy, fibromyalgiaa is consideredd as a central sensis
tization syyndrome, andd it is acknowlledged that thhere is
an abnorm
mal pain processing [7]. Allthough the prrecise
mechanism
ms underlyingg fibromyalgiia pathophysioology
are still not
n completelly understoodd, it is knownn that
both geneetic and enviroonmental factors are involvved in
the develoopment of the disease.
Fibrom
myalgia, both ddue to the facct that it is a m
multisymptomaatic disease ass for its frequuent comorbidiity, is
associatedd to increasedd healthcare ccosts in relatiion to
patients eexperiencing other diseasees [8-10]. Pattients
quality off life is low; although this has been reelated
more withh the psychollogical distresss associated tto the
disease thhan to the limiitations of theiir physical funnction
[11-12], a recent study found that thhe intensity off pain,

along with aanxiety and deepression sym

mptoms were thhe
most relevannt explanatory variables assoociated with thhe
impact of fibbromyalgia onn the quality oof life of the pap
tients [13].
Such a coomplex diseasee is not easy to treat and, in
fact, not a sinngle therapeutic modality hhas shown to bbe
fully effectivve to improve the disease. T
The objective of
the present aarticle is to revview the diffeerent therapeuttic
options availlable for the treatment
t
of ppatients with fibromyalgia.

Pharmac
cologic T
Therapy
The current cclinical practiice in fibromyyalgia is limited
by the complex nature of the disease. T
This is reflected
by the lack of a single aagent able to control all thhe
a in the lim
mited number of
symptoms off the disease and
available phaarmacotherapiies that are aapproved by thhe
drug regulatoory authoritiess for the treatm
ment of fibrom
myalgia. Whilee only three ddrugs have been approved bby
the US Food and Drug Addministration (FDA),
(
pregabbalin in 2007, duloxetine iin 2008, and milnacipran in
n
2009, the Euuropean Mediccines Agency (EMA) has not
granted the aapproval for aany drug so farr. The currenttly
available theerapeutic options for the ttreatment of fibromyalgia are
a discussed bbelow.

Antidep
pressants
s
Besides theirr role in the m
management off depression annd
anxiety disorrders, antideppressants are effective in thhe
treatment off chronic painn modifying bboth the centrral
and peripherral sites involvved in pain trransmission annd
perception (T
Table 1) [14, 15]. Several clinical studiies
have investiggated the efficaacy of the varrious antidepreessant classes in
i the treatmeent of fibromyyalgia, includinng
tricyclic antiidepressants (T
TCA), serotonnin and noreppinephrine reupptake inhibitorrs (SNRI), andd selective serrotonin reuptakke inhibitors (S
SSRI) (Table 2).

Tricyclic A
Antidepresssants
Tricyclic anttidepressants ((TCA) are onne of the oldeest
antidepressannt classes. Thheir clinical usse has not been
restricted to depression, ass they are widdely used in different chronnic pain condditions includiing neuropathhic
myalgia [15]. In
pain, headachhe, low back ppain and fibrom
a recent metta-analysis thaat evaluated thhe efficacy annd

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Treattment of fib
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safety of antidepressannts in the treatm

ment of fibrom
myalRIs, and SNR
RIs were assocciated
gia, eitheer TCAs, SSR
with signiificant improvvement at the llevel of pain, ssleep,
fatigue, depression
d
andd health-relatted quality off life;
however the TCAs hadd the largest effect sizes inn improving ppain and sleep disturbances as compared tto the
other classses [16-17]. Inn another metta-analysis com
mparing amitrriptyline with duloxetine and
a
milnaciprran, it
was foundd that amitripptyline was suuperior in redducing
pain, sleeep disturbancces, fatigue and health-reelated
quality off life; howeverr, and due to tthe methodoloogical
limitationns of the trialss (small numbber of patientts and

short-termed studies), the authors conccluded that am

mitriptyline couuld not be reggarded as the ggold-standard in
the treatmentt of fibromyaalgia [18]. Thiis fact confirm
ms
the need for well-designed
w
d, long-term clinical trials abble
to evaluate the
t actual effficacy of amiitriptyline in fibromyalgia. The doses off TCAs show
wing efficacy in
mmended for thhe
fibromyalgiaa are lower thaan those recom
treatment of major depresssive disorder, w
which is not thhe
case for otheer antidepresssant classes; tthis is probabbly
due to their m
multiple mechanisms of actiion, both at ceentral and periipheral sites, iinvolved in thheir capacity to
counteract paain-generatingg mechanisms [15].

Table 1. Pharmacologic
P
c actions of anntidepressants in relation wiith persistent ppain signaling*
Mechaniism of Action
n

Sitte of action

TCA

SNRII

SRI

Reuptakee inhibition off Monoamine

Seerotonin

Nooradrenaline

Receptorr Antagonism

-A
Adrenergic

NM
MDA

(+) milnacipran
m

Soodium channell blocker

(+) vvenlafaxine
dulooxetine

(+) fluoxetinee

Caalcium channeel blocker

m
(+) citalopram
fluoxetine

Pootassium channnel activator

GABAB rreceptor

Inccrease of recepptor function

+ amitripttyline
desipramiine

+ fluoxetine

Opioid
bindreceptor
ing/opioiid-mediated efffect

- and -Opioid receptor

(+)

(+) veenlafaxine

(+) paroxetinee

Blocker or activator of ion

channels

Abbreviattions: SNRI= serotonin and norepinephrinne reuptake innhibitor; SRI= selective serootonin reuptakee inhibitor;
TCA= triccyclic antideprressant; + indiicates mechannism of action documented iin vitro and/orr in vivo; (+) inndicates mechhanism of action
a
documeented in vitro aand/or in vivo at high conceentration; inddicates no knoown mechanism
m of action; ?
indicates nnot investigateed/not known
*: Adapteed from referennce [15]

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Treattment of fib
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Table 2. Effect
E
sizes off the different classes of antiidepressants oon different fibbromyalgia sym
mptoms*
Outcomee

Efffect Size (95%

% CI)**
TC
CA

SSRI

SN
NRI

Pain

-1.64 (-22.57 to -0.71)

-00.39 (-0.77 to -0.01)

-0.36 (-0.46 to -0.25)

Fatigue

-1.12 (-1.87 to -0.38)

-0.17 (-0.47 to 0.12)

-0.08 (-00.20 to 0.05)

Sleep

-1.84 (-22.62 to -1.06)

-0.23 (-0.56 to 0.10)

-0.31 (-0.47 to -0.14)

Depressed mood

-0.60 (--4.53 to 3.33)

-00.37 (-0.66 to -0.07)

-0.26 (-0.42 to -0.10)

HRQOL

-0.31 (-00.60 to -0.01)

-00.41 (-0.78 to -0.05)

-0.31 (-0.44 to -0.17)

Abbreviattions: CI= Confidence Interrval; TCA= Trricyclic antideepressant; SSR

RI= Selective serotonin reupptake inhibitorr;
SNRI= Seelective serotoonin norepinepphrine reuptakke inhibitor; H
HRQOL= Heallth-related quaality of life.
*: Adapteed from referennce [17]. **: S
Small = 0.2-0.49; Medium = 0.5-0.79; Laarge 0.8

Selectivve Seroton
nin Norepin
nephrine
Reupta
ake Inhibito
ors
To date, the three SN
NRIs that havee been tried iin the
treatment of fibromyallgia are venlaafaxine, duloxxetine
with similar afffinity
and milnaacipran. The latter blocks w
the reuptaake of serotoonin and noraadrenaline whhereas
duloxetinee shows a 10--fold selectiviity and venlaffaxine
a 30-fold selectivity foor serotonin [119]. In spite oof the
NRI to be studiied in
fact that vvenlafaxine waas the first SN
fibromyallgia, it has nott been extensivvely investigatted in
this indication as it has been shownn to be effectiive in
mptoms only inn two
alleviatingg pain and deepressive sym
small unccontrolled triaals [20-21]. Duloxetine
D
600-120
mg/day and
a
milnaciprran 100-200 mg/day
m
have been
shown too significantlyy reduce paiin and depreessive
symptomss and to improove quality off life; while duuloxetine theraapy lead to siignificant impprovement in sleep
disturbancces, it had nnon-significantt effect on faatigue
that was, on the other hand, significcantly improveed by
wn to
milnaciprran [18, 22]. Duloxetine hhas been show
reduce paain and other symptoms off fibromyalgiaa both
in patientts with or witthout major ddepressive dissorder
[23]. In ccontrast to the short-term sttudies investiggating
the effectt of TCAs inn fibromyalgiia, duloxetinee and
milnaciprran have been studied in 1-year folloow-up

studies, wherre their efficaccy has been shhown to be prreserved over the entire perriod for both antidepressannts
with a good ttolerability andd safety profille [24-25].

Other Anttidepressan
nts
Selective serotonin reuptakke inhibitors aare not as effeective as the otther antidepreessants in the treatment of fibromyalgia. In the meta-aanalysis perforrmed by Husser
and coworkeers [16] althouugh the effeccts of SSRIs oon
pain, sleep, ffatigue depresssion and quallity of life weere
statistically significant,
s
theeir effects sizees were found to
be small or nnon-substantiall. The same reeason promotinng
the tolerabiliity of SSRIs in clinical praactice might bbe
the factor leaading to their inferiority
i
in tthe managemeent
of chronic paain conditions, as their selecctivity to inhibbit
one monoam
mine system m
makes them lesss efficacious in
treating chroonic pain condditions as com
mpared to TCA
As
[26]. Howeveer and followiing the conceppt of individuaalized patient ccare, SSRIs could be benefficial in fibrom
myalgia patiennts presenting concurrent deepressive sym
mptoms and theey remain to bbe the drugs oof choice in pap
tients who arre not able to tolerate
t
other antidepressannts.
Trazodonee, an old secoond generationn antidepressaant
with significaant sedative activity,
a
is freqquently used, in
an off-label bbasis, in the trreatment of inssomnia in manny
countries. Trrazodone was recommendedd by the Amerri-

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Treattment of fib
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can Pain Society for uuse in patients with fibromyyalgia

minent sleep ddisturbances. A small two-m
month
with prom
double-blind controlledd crossover stuudy, only publlished
in an absttract form, fouund that trazoddone use in fibbromyalgia waas associated with
w improvem
ments in sleepp disturbances, but had not aany significannt effect on psyychoms [27]. Laterr, two
logical prrofile and clinnical symptom
uncontrolled studies haave been publlished. The fiirst of
them founnd that trazodoone, in a flexiible dose up too 300
mg/daily, improved sleeep quality, aanxiety and deepression but hhad no effectt on pain [28]. The secondd one
found thaat the additioon of pregabbalin to trazoodone
treatment potentiated tthe antidepressant efficacyy and
improvedd pain, with thhe combinationn of the two drugs
being welll tolerated [299].

Anti-e
epileptics
s
To use thhe term antieppileptics is prrobably misleading
since only one class oof antiepilepttic drugs, thoose of
calcium cchannel modullators, has beeen shown to bee useful in the management of fibromyalggia. Pregabalinn and
gabapentiin play a crritical role inn pain perceeption
through tthe modulationn of 2 volttage-gated callcium
channel thhat leads to thhe inhibition of the synapttic release of gglutamate, subbstance P andd other neurottransmitters m
mediating pain response [300]. They are w
widely
used in seeveral chronicc pain conditioons both in Euurope
and in thee United Statees. Pregabalinn is FDA-apprroved
for the ttreatment of diabetic perippheral neuroppathy,
postherpeetic neuralgia, neuropathic pain due to sspinal
cord injurry and fibrom
myalgia, and E
EMA-approveed for
peripherall and centraal neuropathhic pain, whhereas
gabapentiin is FDA-appproved only fo
for the treatmeent of
postherpeetic neuralgiaa and EMA--approved forr the
treatment of peripheraal neuropathicc pain. Pregaabalin
shows beetter pharmacokinetic and pharmacodynnamic
profiles [331] making itt preferable too gabapentin (stud(
ied in onlyy one small 122 week random
mized clinicall trial)
that couldd be considereed in patients who
w are respoonsive
but cannoot tolerate pregabalin. Theirr use in fibrom
myalgia is suppported by tw
wo recent metaa-analyses [322-33].
Both druggs have been found to reduuce pain and tto improve sleeep and health--related qualitty of life; how
wever,
they show
wed non-substaantial effect oon fatigue and anxiety and laacked effect onn depression w
with adverse events
e
that includded dizziness,, somnolence, dry mouth, w
weight

gain and periipheral edemaa. The evidence for pregaballin

efficacy is strronger than thhe one for gabaapentin.

Analges
sics
Non-stero
oidal Anti-in
nflammatorry Drugs
Although paiin is the cardinnal symptom of
o fibromyalgiia,
NSAIDs do not contributee significantlyy to its managgement, whichh is not ssurprising given the nooninflammatoryy nature of thhe disease. Allthough the evvidence concerrning their efffectiveness in tthe treatment of
fibromyalgiaa is limited, ccontrolled triaals have show
wn
little or no eefficacy eitherr when administered alone or
combined w
with other druugs such as aamitriptyiline or
benzodiazepiines [34-37]. H
However, theyy are still wideely
used, althouggh they are noot perceived aamong the moost
effective meddications [38]..

Opioids
Clinical trialls evaluating the efficacy of opioids aare
limited to a vvery small douuble-blind triaal of intravenoous
morphine shhowing no effficacy and loow tolerabilitty.
However, deespite the factt that there iss no convincinng
evidence of eefficacy, opiooids are frequeently prescribed
for the treatm
ment of pain inn fibromyalgiaa in many couuntries [39]. A
An uncontrolleed study, pubblished only in
abstract form
m, did not findd evidence off pain improvvement during a four-year fo
follow-up of fi
fibromyalgia ppawo
tients treatedd with opioidds but found that, after tw
years of treaatment, depresssion increasedd [40]. The uuse
of opioids inn fibromyalgiaa is also probblematic due to
their side-efffect profile; inn addition to the risk of ded
pendence, thhere is also of
o concern thhe constipatioon,
considering tthat this is a very commoon symptom rreported by pattients with fibbromyalgia whhose comorbiddity with irritabble bowel synndrome is highh; likewise, oppioids sedationn and mental clouding
c
may w
worsen the coognitive dysfunnction experiennced by many patients [39].

Other Ana
algesics
Tramadol is a drug that actts both as agonist on opiooid
receptors andd as inhibitor of serotonin and noradrennaline reuptakee. It has been shown to be effective in thhe
management of pain in fibbromyalgia both as monotheerapy [41] andd combined wiith paracetamool [42]. The uuse
tramadol or tramadol-paraacetamol combbination for thhe

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Treattment of fib
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treatment of pain shoould be betterr reserved foor as

medication, foor periods of fibromyalgia flareneeded m
ups, ratheer than for chroonic use.
Tapentaadol, a centraally-acting anaalgesic, is struucturally relateed to tramadol; it has higheer affinity thaan tramadol forr receptors aand inhibits thhe reuptake of noradrenaline but not of serotonin [43]. It has shown to be
effective in different tyypes of chronnic non-cancerr pain
with betteer tolerability than pure -opioid receptorr agonists [44]. Although it seems a prom
mising drug foor the
treatment of pain in fibromyalgia, iits potential roole in
this indicaation awaits fuurther investiggation.

Otherr drugs
Cyclobe
enzaprine
Cyclobennzaprine, licennsed as a musscle relaxant, is an
TCAs. In a m
metaold drug structurally similar to T
analysis including 5 randomized, placebo-contrrolled
trials, cycclobenzaprinee demonstrateed effectiveneess in
improvingg sleep, and modestly
m
impproving pain iin the
early stagges of treatmeent, but it didnnt improve faatigue
or tender points [45]. F
Favorable outcomes of veryy low
dose cyclobenzaprine ((1- 4 mg) weree achieved in an 8week, double-blind, pllacebo-controllled trial, where it
mproved pain, tenwas assocciated with siignificantly im
derness, ddepressive sym
mptoms, and iincreased nighhts of
restorativee sleep [46].

Sodium
m Oxybate
Sodium oxybate, thhe sodium salt of gam
mmao
drug status
hydroxybutyrate that ggained FDA orphan
management of cataplexy annd daytime slleepifor the m
ness in paatients with naarcolepsy, hass been shown to be
effective for the treatm
ment of fibromyyalgia in four large
randomizeed controlled clinical trials; however, it failed
to gain thhe FDA approoval for use inn fibromyalgia due
concerns of potential abbuse [47]. In all
a of these stuudies,
sodium ooxybate improoved outcomees of pain, fattigue,
sleep distturbances, Fibbromyalgia Im
mpact Questionnnaire
scores andd the patient gglobal impression of change [48].

Sedativve-hypnoticcs
The sugggested role of sedative hypnotics in the management of fibromyalggia arises from
m the major sleep

disturbance that this grooup of patiennts experiencees.

Knowing thaat a positive association exists between
poor sleep annd pain and ffatigue [49], iimprovement of
sleep symptooms was exppected to be associated wiith
better outcom
mes on pain aand other fibroomyalgia sym
mptomatology. However, som
me benzodiazzepines, temazzemazepam, havve been tried in
pam, alprazoolam, and brom
the treatmentt of fibromyalgia with little or no result [336,
37, 50]. Also, the two noon-benzodiazeepine GABA--A
b
agonists zolppidem and zoopiclone, imprroved sleep but
neither pain nor mood diisturbances [551-53]. Thus, it
seems that thhe role of thesee drugs in the management of
fibromyalgiaa is very limiteed.

Dopamine
e Agonists
The evidencee for a possible role of the D2 dopamineergic agonists in
i the treatmennt of fibromyaalgia is confliccting. A randoomized controolled trial wiith pramipexoole
found that thhe drug improoved pain, fatiigue and globbal
well-being [554]. However,, two additionnal clinical triaals
evaluating roopinirole andd extended-rellease ropiniroole
failed to findd any treatmeent-related beenefit [55]. Onne
trial with extended-release pramipexole (NCT006890552)
with rotigotinne
was early terminated aand other w
(NCT004647737), has beenn completed buut not published
[56-57].

5-HT3 Antagonists
Several trialss with intraveenous or oral tropisetron annd
one with inttravenous dollasetron in thhe treatment of
fibromyalgiaa have been puublished showiing a significaant
decrease of pain
p levels. Thhe use of thesee drugs has been
advocated m
mainly for patiients sufferingg high levels of
pain and nott showing rellevant psychoological distreess
[58].

One Dru
ug or Com
mbination
n Therap
py?
As there is nnot a drug ablee to control alll the symptom
ms
of the diseasse, the possibiility to adminnister more than
one drug sim
multaneously seems logicaal and, in facct,
several studiies have found that in the routine cliniccal
practice, patiients receive a mean of 22-3 concomitaant
drugs [59-61]. However, and
a in contrastt with the abuundance of puublished monootherapy cliniical trials, litttle
information is available cconcerning thhe efficacy annd

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Treattment of fib
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tolerabilitty of drug com

mbinations. Thhus, when considering polythherapy, therappeutic decisionns must be bassed on
data from
m monotherapyy trials and a soound knowleddge of
the pharm
macological profile of eachh drug in ordder to
combine ddrugs that impprove differennt symptoms oof the
disease while
w
avoidingg the overlappping of side effects
[62].

Non-pharmaco
ologic Th
herapy
Several nnon-pharmacoologic treatm
ment options have
been show
wn to be effecctive as part oof the manageement
of fibromy
myalgia, and thhey are currenttly regarded ass fundamental components iin the treatmeent plan of fibbromyalgia pattients.

Educa
ation
Educationn is viewed aas a basic com
mponent of a welldesigned therapeutic pplan in fibrom
myalgia. This intervention is characterizeed by an infformative rolee that
wareness abouut the
aims toward increasingg patients aw
various aaspects of thee disease, succh as the possible
pathogeneesis and its correlation with
w
the diff
fferent
symptomss, the role off pharmacologgic therapies in fibromyalgia and the exttent of the beenefit they proovide,
in additionn to the possibble lifestyle faactors and actiivities
that mighht alleviate orr exacerbate fi
fibromyalgia ssymptoms. How
wever, clinicaal trials assessiing the role off education in fibromyalgia have evaluateed this interveention
t
mostly ass an add-on off other non-phharmacologic therapies exceppt in four conntrolled clinicaal studies that evaluated the discrete role and benefit off education. BurckB
hardt, et aal. [63] compaared educationn alone and education plus physical trainning with a w
waiting-list coontrol
group andd found a signiificant positive impact on quuality
of life and self-efficacyy for both inteerventions as compared to tthe control grooup. Bosch, ett al. [64] evalluated
the impacct of educatioon versus no iintervention inn two
groups off patients withh fibromyalgiia; they foundd that
the educaation group im
mproved only iin the perceptiion of
body painn. Rooks, et all. [65] comparred education alone
with two kinds of exerrcise programss and the com
mbination of edducation and exercise; theyy found all off four
groups im
mproved but tthat the degreee of improveement
was higheest in the combbination groupp. Stuifbergen, et al.
[66] com
mpared educattion alone wiith education plus

lifestyle chaanges and again it was fo

found that booth
groups improoved along the time but thaat the combined
group improoved more in physical actiivity and streess
management.
Although the available evidence is limited, the rresults of thesee studies suppoort a modest bbeneficial role of
education thhat also seem
ms to potentiiate other noonpharmacologgic interventionns. Thus, educcation would bbe
mostly indiccated in multiimodal therappeutic interveentions.

Exercise
e
The role of exercise has been widely studied for iits
myalgia. The tyypes of exerciise
potential bennefits in fibrom
interventionss that have been investigateed in fibromyaalgia include aerobic exerccise (land-bassed and wateerbased), strenggth, and flexibbility, and diffferent combinnations of thesse, with aerobbic exercise bbeing the moost
investigated intervention. Exercise inteerventions in fibromyalgia hhave been gennerally found tto be associated
with decreassed pain intennsity, reducedd severity of fibromyalgia symptoms, annd improved emotional annd
mental healthh [67]. Combbined exercise modalities annd
aerobic exerrcise are the interventionss that have thhe
strongest eviidence of bennefit in patiennts with fibrom
myalgia [68]. A meta-analyysis evaluatingg the effects of
the different types of aeroobic exercise ((land-based annd
water-based) showed that both types of physical activvities significaantly improved pain, depreessed mood, ffatigue, qualityy of life and physical
p
fitnesss but had noonsignificant innfluence on slleep disturbannces [69]. A rreview aiming to evaluate w
which kind off physical exeern
cise is best ffor fibromyalggia found thatt there were not
clear differennces in the eefficacy of either land-based
aerobic exerrcise, water-bbased aerobicc exercise annd
muscle strenngthening, altthough water--based exerciise
and strengtheening seemed to be slightlyy more effectivve
in reducing spontaneous
s
paain and depresssive mood [770].
Despite not being frequenntly reported, adverse effeccts
w
exercise therapy such as increase in
associated with
symptoms (ppain, stiffnesss and fatigue)) and musculloskeletal probblems should bbe also evaluaated and consiidered [67]. Acccordingly, it is recommennded to considder
individualizeed plans of exxercise therapiies that are prrimarily determ
mined by the patients preference and aaccessibility; thhese plans shoould cover thee specific physsi-

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Treattment of fib
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cal needs of the patient and ensure addequate complliance

in order too avoid attritioon that is frequuently reportedd.

Psych
hotherapy
y
The mostt studied psyychotherapeutiic approach iin fibromyalgia is the cognnitive behaviooral therapy (C
CBT).
mbines cognitivve and behavvioral therapies that
CBT com
are intendded to assist ppatients in buillding a set of skills
to encounnter dysfunctioonal emotionss, thoughts annd behaviors [771]. Pain cataastrophizing reepresents the characterizatioon of pain ass being awfull, horrible andd unbearable, a feature that suggests psycchological vullnerability andd constitutes a major contriibutor to the exaggeration oof pain experiience and depression [72]. Compared to ppatients with rheumatoid arthritis,
a
fibrom
myalgia patieents show a significantlyy more prom
minent
catastrophhizing profile,, suggesting thhe need for cognic
tive theraapy and coping skills [73]. In a meta-anaalysis
including 23 studies thaat evaluated ddifferent psychhologments in patieents with fibrromyalgia, psyychoical treatm
therapy efffectively reduuced sleep prooblems, depresssion,
functionall status, and catastrophizing
c
g with CBT hhaving
the greateest effect size compared to oother psycholoogical
interventions (relaxatioon, educationn, behavioral treatmindfulness-baased treatmentts, and eye movem
ments, m
ment deseensitization annd reprocessinng) [74]. In annother
meta-anallysis including 14 random
mized clinical trials
specifically investigatiing the efficaacy of CBT in fibromyalgia, CBT was associated w
with significannt decrease in depressive syymptoms, selff-efficacy painn (i.e.
subjects perceived abbility to manaage and cope with
pain and its emotionall and behaviooral consequeences)
and the nnumber of phyysician visits aat follow-up; however, non-significant efffects on pain, sleep, fatiguue and
Therehealth-related quality oof life were obbtained [75]. T
fore, it caan be concludded that psychhotherapeutic intervention remains an esssential compoonent in the treatment of ffibromyalgia ggiven the psycchological vullnerability of fi
fibromyalgia ppatients.

Compllementarry and Allternative

e
Medic
cine
As there iis no cure for fibromyalgia
f
aand as the avaailable
therapies offer only parrtial efficacy, patients frequuently
CAM)
turn to complementary and alternativve medicine (C

looking for additional

a
reliief [76-77]. C
CAM is a broad
term which encompasses a huge varieety of therapiies
that are not ggenerally conssidered to be part of the coonventional meedicine and thhat patients caan use togethher
with it (hencce the expresssion complemeentary) or in its
place (hence the expressioon alternative)). The U.S. N
National Instituttes of Health bbroadly classiffies CAM in thhe
following fouur categories [[78]:
- natural products: such ass herbal mediicines, vitaminns,
minerals, dietary supplemeents and probiootics.
- mind and bbody medicinee: including aacupuncture, rrelaxation techhniques, qi goong, tai-chi oor hypnotherappy
among the m
most known.
- manipulatiive and bodyy-based practtices: includinng
spinal manippulation and massage therrapy among thhe
most frequenntly used.
- other CAM
M practices: thhat include m
movement therrapies, traditioonal healers ppractices, eneergy fields, annd
whole medical systems.
Many CA
AM therapies have never been
b
adequateely
investigated for efficacy and among those
t
that havve
been studiedd, there were usually few trials of smaall
sample size. A recent meta-analysis oof CAM in thhe
treatment of fibromyalgia found that onnly balneotherrapy had effectt sizes indicatting that they reduced pain in
fibromyalgiaa [79]. Massagge, acupuncturre and nutritioonal supplemennts showed noo clear evidennce of efficaccy.
Finally, maniipulative, vibrration, magnettic, homeopathhy,
movement thherapy and ennergy medicinne had 3 or leess
trials and could not be annalyzed. Thus, it seems cleear
that additionaal studies are needed to evaaluate the valuues
of the differeent CAM therrapies in the management of
fibromyalgiaa.

Multi-co
omponentt Treatment
The complexxity of fibrom
myalgia and its overlappinng
pathophysiological mechannisms makes difficult to coontrol the broadd range of the disease sympptoms. All of thhe
pharmacologgic and non-ppharmacologicc options prevviously mentiooned are assocciated with a liimited extent of
improvementt in fibromyyalgia symptoomatology, annd
none of them
m provides ssufficient bennefit when prre-

229

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Treattment of fib
bromyalgia

scribed allone. Thereforre, it is widelly accepted am

mong
healthcaree professionalls that a patiient-specific m
multicomponennt therapeuticc approach inncluding both nonpharmacoologic and phaarmacologic ttherapies shouuld be
employedd to attain optim
mal clinical ouutcomes. Giveen the
distinct m
mode of activitty of each typee of interventiion, it
makes sennse to combinne them for obbtaining a maxximal
benefit of
o symptomatic improvem
ment. In a m
metaanalysis iincluding 9 R
RCTs with 1,119 subjects, iit was
shown thaat a multi-com
mponent theraapy with at leeast 2
non-pharm
macologic theerapies (at least 1 educationnal or
other psycchological theerapy and at leeast 1 exercisee therapy) was associated wiith strong evidence for redducing
fitness
pain, fatiigue, depressiive symptomss, physical fi
and limitaations to healthh-related quality of life [80]]. In a
recent ranndomized clinnical trial asseessing the effficacy
of multidiisciplinary treeatment (conveentional pharm
macologic treaatment, CBT, and physicall therapy) verrsus a
control ggroup receivinng conventionnal pharmacoologic
treatment only in wom
men with low educational
e
levvel, it
was founnd that improovements in ffunctionality, sleep
disturbancces, pain inteensity, catastrrophizing andd psychologicaal distress weere significanttly superior in the
multidisciiplinary treatm
ment group aand that impprovements of sleep disturbbances, catastrrophizing andd psychologicaal distress were maintainedd at 12-monthh follow-up [881]. The strenngth of evidennce supportinng the
adaptationn of multidiscciplinary apprroach in fibrom
myalgia is a m
moderate to strrong evidencee; however it iis not
yet know
wn which com
mbinations best provide the optimal beneffit in fibromyyalgia [82]. Vaarious combinnation
approachees are possiblee, and the selection of thesse options reliees on the specific patientss needs on thee one
hand and on the patiennts accessibiliity to the sugggested
treatment options on thhe other hand. At least, the combination oof pharmacoloogic therapy aand exercise shhould
be mandaatory; patientss education and/or
a
CBT shhould
be added whenever posssible.

approach inccluding both pharmacologgical and noonpharmacologgic therapies is required for optimizinng
treatment ouutcomes. In adddition, there is a clear need
for more reseearch on indivvidual therapiees and treatmeent
combinationss.

Disclosu
ure
There are no conflicts of innterest.

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