15

Multidisciplinary approach to bromyalgia: What is

the teaching?
Piercarlo Sarzi-Puttini, MD
a,
*
, Fabiola Atzeni, MD, PhD
a, b
, Fausto Salaf, MD,
PhD
c
, Marco Cazzola, MD
d
, Maurizio Benucci, MD
e
, Philip J. Mease, MD
f
a
Rheumatology Unit, L. Sacco University Hospital, Ospedale L. Sacco, Via GB Grassi 74, 20127 Milano, Italy
b
Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
c
Rheumatology Department, Polytechnic University of the Marche, Ancona, Italy
d
Unit Operativa di Medicina Riabilitativa, Azienda Ospedaliera Ospedale di Circolo di Busto Arsizio Presidio di Saronno,
Varese, Italy
e
Rheumatology Unit, Ospedale San Giovanni di Dio, ASL 10, Florence, Italy
f
Rheumatology Research, Swedish Medical Center, University of Washington School of Medicine, Seattle, WA, USA
Keywords:
Fibromyalgia
Interdisciplinary management
Drugs
Fibromyalgia (FM) is a rheumatic disease that is characterised by
chronic musculoskeletal pain, stiffness, fatigue, sleep and mood
disorder. FM patients demonstrate dysregulation of pain neuro-
transmitter function and experience a neurohormone-mediated
association with sleep irregularities. There are currently no instru-
mental tests or specic diagnostic markers for FM, and many of the
existing indicators are only signicant for research purposes. Anti-
depressants, non-steroidal anti-inammatory drugs (NSAIDS),
opioids, sedatives, muscle relaxants and antiepileptics have all been
used to treat FM with varying results. It has been shown that inter-
disciplinary treatment programmes lead to greater improvements in
subjective pain and function than monotherapies. Physical exercise
and multimodal cognitive behavioural therapy are the most widely
accepted and benecial forms of non-pharmacological therapy.
2011 Published by Elsevier Ltd.
Introduction
Fibromyalgia (FM) is a generalised chronic pain condition that is often accompanied by fatigue, sleep
disturbance, and psychological and cognitive alterations [1,2]. It is the prototypical form of a central
sensitisation syndrome [1] and prevalence studies show that it affects 24% of the population (approxi-
mately half a million Italians). It is more common among adult women, but may also affect men and
children.
* Corresponding author.
E-mail address: sarzi@tiscali.it (P. Sarzi-Puttini).
Contents lists available at ScienceDirect
Best Practice & Research Clinical
Rheumatology
j ournal homepage: www. el sevi erheal t h. com/ berh
1521-6942/$ see front matter 2011 Published by Elsevier Ltd.
doi:10.1016/j.berh.2011.03.001
Best Practice & Research Clinical Rheumatology 25 (2011) 311319
There are currently no instrumental tests or specic diagnostic markers, and the characteristic
symptoms of the disease overlap those of many other conditions [3]. However, it is becoming more
manageable as a result of the use of more rational evidence-based pharmacological therapy and
a growing awareness that therapy needs to go beyond pain. Many studies have found that patients with
FM are less physically t than control groups of the same age, gender and occupation [4,5]. The
functional limitations reported by patients include reduced exercise tolerance, fatigue, and pain
exacerbations caused by the activities of daily living (ADL) [6], which means that non-pharmacological
therapeutic strategies aimed at improving aerobic tness, muscular strength and endurance may be
important in reducing disease-related disabilities [7,8]. The effective management of FM is complex
and requires a multidisciplinary approach, and it has been shown that integrated treatment, including
appropriate patient education, aerobic exercise and cognitive-behavioural therapy, is effective in
alleviating symptoms.
Diagnosis
FM is usually diagnosed in clinical and observational research studies on the basis of the American
College of Rheumatology (ACR) criteria [9]: pain must have been present for at least three months in all
four quadrants of the body, and there must be >11/18 positive tender points (TPs) revealed by applying
pressure (4 kg/cm
2
) at pre-dened body sites. However, these criteria do not take into account the wide
range of symptoms commonly associated with FM, and reected by the term syndrome, including
sleep disturbance, depression, anxiety, fatigue, cognitive dysfunction, morning stiffness, irritable bowel
syndrome, headache and migraine. Some recently proposed diagnostic criteria that assess widespread
pain as well as the severity of fatigue, sleep disturbance and cognitive dysfunction, and the extent of
somatic symptoms, may improve diagnosis and treatment. Wolfe et al. have proposed simple clinical
criteria that do not require the use of TPs and extend the denition of FM to include symptoms other
than pain and provide a means of assessing their severity [10]. Moreover, a diagnosis is made by
combining the patients history with a physical examination and laboratory tests, and excluding or
accounting for other causes of the symptoms attributed to FM [2,11]. As FM overlaps a number of other
medical conditions, ranging from rheumatoid arthritis and lupus to hepatitis C infection, treating
physicians need to be carefully analytic in the general evaluation of all patients with suspected FM.
Inter-disciplinary treatment
The aim of treating FM is to decrease pain and increase function by means of a multimodal ther-
apeutic strategy which, in most cases, includes pharmacological and non-pharmacologic interventions
[12] and has the main goal of symptom management [13]. As FM patients typically present complex
symptoms and comorbidities, they cannot realistically be managed by primary care physicians alone,
but require the assistance of multidisciplinary teams with expertise in a variety of physical, cognitive,
behavioural and educational strategies [14].
Most of the directors of multidisciplinary treatment programmes are rheumatologists or rehabili-
tation specialists, but there is no reason for excluding other health professionals. Some of the pro-
grammes mainly based on promoting cognitive-behavioural changes only involve rheumatologists and
psychologists or psychiatrists, who are often considered essential because most FM patients have
difculties in dealing with stress and interpersonal problems, and are at increased risk of developing
depression or anxiety [1519]. As exercise is a critical part of FM treatment and a key element in
successful cognitive behavioural therapy, most programmes would benet from the addition of an
exercise physiologist or physical therapist with expertise in prescribing stretching, aerobic condi-
tioning and strength training exercises [1921]. Other possible team members consultants are social
workers, occupational therapists, sleep or headache specialists, or massage therapists [14].
Education and psychological domains
A number of the techniques used in the management of FM are based on patient education, and are
intended to reduce anxiety, increase treatment compliance, improve coping behaviours and self-
P. Sarzi-Puttini et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 311319 312
efcacy, and drawattention away from symptoms and towards improved function and a better quality
of life. It has long been recognised that patients have an essential right to education, and the ndings of
this review suggest that they should be offered exercises and education (including information and
cognitive-behavioural strategies) by a multidisciplinary team in a group format [14].
One of the aims of a multidisciplinary approach should be to switch patients perceptions from
helplessness, frustration and sometimes anger, to a positive sense of behavioural self-efcacy and
outcome expectancies [12]. Self-efcacious patients are more likely to respond favourably to treatment
programmes and experience better outcomes [17], whereas many patients believe that they cannot
control their pain, disability or other negative effects (which leads to increased distress, pain and sleep
difculties), tend to take less part in daily living activities, and fail to develop effective coping
behaviours and cognitions.
Psychological interventions involve the interrelationships between the physical and psychological
aspects of the illness [19]. Two major approaches are psychophysiologically-based therapy (PPT), such
as electromyography (EMG) biofeedback, and cognitive-behavioural therapy (CBT). The basic aim of
PPT is to change cognitions by manipulating physiological responses, whereas the aim of CBT is to
change physiological responses by manipulating cognitions in order to help patients feel that they are
in control [18,19].
CBT is a combination of cognitive and behavioural therapies, and may have a wide range of
components. The behavioural components include a number of techniques centred on the core tenets
of operant and classical psychological conditioning, and may be extended to methods such as relax-
ation, sleep hygiene, pacing activities, scheduling social and leisure opportunities, coping with pain,
education, and training in assertiveness [22], all of which go to make up the CBT toolbox. This concept
is important when considering CBT for FM patients because any meaningful discussion and evaluation
must take into account the tools that are used.
Comorbidities such as stiffness, fatigue and problems with sleep, concentration and memory are
more or less common in almost all FM patients. It is not surprising that many patients experience
interpersonal distress and behavioural decits and, as CBT is particularly effective in the case of distress
and behavioural disorders, it is logical to apply it to FM. This approach assumes that a patient can be
helped signicantly by addressing the many non-pain aspects of FM.
Pharmacologic treatments
Once a diagnosis of FM is made, patients are usually started on pharmacological treatment.
Boomershine and Crofford [23] suggest that the three drugs currently approved by the American Food
and Drugs Administration (FDA) should now be used as anchor drugs and, although still important,
could later be complemented by older approaches. Unfortunately, no direct comparative studies have
yet been published, and there is still no consensus as to where to start.
FM patients experience amplied ascending sensory input; mediated by excess amounts of
neurotransmitters such as glutamate and substance P, which can be reduced by medications such as
pregabalin. In parallel, deciencies in the diffuse noxious inhibitory control system (DNIC), the
descending pain regulation pathways which play an inhibitory role in pain perception and are medi-
ated in part by the neurotransmitters serotonin and norepinephrine, can be treated using serotonin-
norepinephrine re-uptake inhibitors (SNRIs). This may be an over-simplication, but it does show that
there are at least two complementary symptom control strategies.
Pregabalin is an a
2
-d ligand that has analgesic, anxiolytic-like and anticonvulsant activity in animal
models, and biochemical studies have found that the primary binding site for pregabalin and the related
gabapentin is a
2
-d (type 1) [24]. Alpha
2
-delta is an auxiliary protein associated with voltage-gated
calcium channels, and the potent binding of pregabalin at the a
2
-d site reduces calcium inux at nerve
terminals [25] resulting in reduction of the release of a number of neurochemicals, including glutamate,
noradrenaline and substance P [25,26], which may explain the analgesic, anticonvulsant and anxiolytic-
like activity of pregabalin in animal models. It has also been suggested that reducing neurotransmitter
release from neurons in the spinal cord and brain may be clinically benecial for FM patients.
Pregabalin is approved for the treatment of FMand neuropathic pain and, in some countries, also for
the management of generalised anxiety disorder and as an adjuvant medication for seizures. The dose
P. Sarzi-Puttini et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 311319 313
indicated for the treatment of FM is 300450 mg/day divided into two administration, although many
clinicians start with smaller nightly doses, as it seems to have a specic benecial effect on sleep
[27,28]. Anxiety is also very common in FM patients and, as patients with concomitant sleep disorders
and anxiety almost always experience initial insomnia, pregabalin is a rational choice. The dose can
subsequently be increased to the recommended dose, but escalation may be limited by side effects
such as weight gain, edema and dizziness that may resolve over time.
Althoughit is not approvedby the FDA, the use of gabapentinhas alsobeenstudiedinFMpatients [26],
and daily doses ranging from 1200 mg to 2400 mg have been found to have some effect. Although the
gabapentintrial involvedfar fewer patients thanthe pregabalintrials, the effect sizes seemedto be similar,
and so gabapentin can be considered an option especially when pregabalin is not available.
The other two FDA-approved medications for the treatment of FM are duloxetine and milnacipran.
Duloxetine is also FDA-approved for depression, generalised anxiety disorder, painful diabetic
neuropathy, and most recently, chronic musculoskeletal pain. Milnacipran is also approved for the
management of major depression in Europe and Japan [29,30]. Both are SNRIs, and it has been
hypothesised that pain, anxiety, chronic stress and depression have overlapping pathogenetic back-
grounds (neurotransmitters and immune responses), and depression can be considered a systemic
disease related to unbalanced neurotransmission also to other neurotrophic, neurosteroidal, central
nervous system (CNS) hormonal modications, and widespread autonomic, immunological and
metabolic somatic changes [31]. According to this hypothesis, antidepressants restore neurotrans-
mitter levels and modulate receptor expression in the hypothalamus, which normalises hyperactivity
of the hypothalamic-pituitary-adrenal (HPA) axis [31]. Autonomic system alterations, such as
sympathetic overactivity, are encountered in both depression and FM [31]. Finally, pro-inammatory
cytokines inside the CNS play a role in the pathophysiology of mood disorders and pain, and their
modulation by means of chronic antidepressant administration contributes to improving both [32].
The trials of duloxetine have shown that 70% of its effect onpain is due to its analgesic rather than its
antidepressant action [29], although it is still is a good choice for patients with FM, depression and
anxiety. The FM dose is 60 mg once a day, but it is usually started at a daily dose of 30 mg. Duloxetine
seems to have a neutral effect on sleep.
The recommended milnacipran doses range from 50 mg twice a day to 100 mg twice a day. It has
been found that it signicantly improves fatigue and cognitive dysfunction, possibly because of its
greater adrenergic effect [30].
Analgesic treatment
Tramadol has been found to be benecial in FM patients [33,34]. It is an atypical pain reliever that
has a different action on the CNS (the re-uptake of serotonin and norepinephrine) from that of other
narcotics. Its most common side effects are drowsiness, dizziness, constipation and nausea, and it
should not be given in combination with tricyclic antidepressants (TCAs). Alone or in combinationwith
acetaminophen, it is commonly prescribed at a dose of 200300 mg/day to relieve FM-related pain
[35,36]. Its potential for drug abuse is fortunately negligible, but there is a theoretical risk of seizures
and serotoninergic syndrome when it is combined with selective serotonin re-uptake inhibitors
(SSRIs), SNRIs, monoamine oxidase inhibitors (MAOIs) and tryptans, although only a few cases have
been described [37].
There is no scientic evidence that NSAIDs alone are effective in FM patients, although they may be
useful for analgesia when combined with TCAs. However, the results obtained when NSAIDs are
combined with benzodiazepines have been inconsistent [3840]. The CNS mechanisms of FM (central
sensitisation and disinhibition, and a dysfunctional HPA axis) may explain the relatively reduced
efcacy of NSAIDs and opioids, particularly as the latter are more effective for peripheral pain [40].
However, NSAIDs can be helpful in reducing pain ares induced by excessive physical activity, tendi-
nitis or bursitis, although they should only be used on an as needed basis in order to avoid side effects.
COX
2
inhibitors have much fewer side effects, but are less effective against pain.
One recent study has found that transdermal buprenorphine, a strong opioid, has benecial effects on
severe widespread pain (VAS >6/10), but it is less effective on the other symptoms typical of FM [41].
P. Sarzi-Puttini et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 311319 314
A subset of FM patients do not respond to opioids, but other patients who may have overlapping
conditions such as diabetes, chronic myofascial pain, temporomandibular joint disorder, arthritis,
degenerative disc disease and so on, may receive a signicant benet [40].
The doses of immediate-release opioids should be increased slowly until the pain is reduced, and
then the patients should be switched to controlled-release opioids.
Opioids may be helpful in treating FM-related pain, but they may also induce tolerance and become
habit forming, and are also associated with adverse effects such as constipation, sedation and nausea
[42]. Physicians should obtain a careful medical and psychological prole of the patient before
prescribing opioids.
Treating fatigue, sleep and mood disorders
Fatigue and sleep disturbances are major complaints among FM patients [2]. Appropriate treat-
ment of sleep disturbances and physical rehabilitation are the best means of managing fatigue in the
long term. The medications commonly used in narcolepsy have been used to treat fatigue in FM
patients [43]. Modanil has been approved by the FDA for the treatment of excessive somnolence
associated with narcolepsy, shift workers and sleep apnea, and can be useful if fatigue prevents
patients from starting physical rehabilitation. The initial dose is 50 mg in the morning, and can be
increased to 400 mg daily, although modanil and other compounds carry a risk of abuse and drug
interactions.
Small doses of the amitriptyline or cyclobenzaprine represent the rst approach to the treatment of
delayed sleep onset in FM patients, but they are only effective in about 30% of cases and most patients
cannot tolerate higher doses because of their sedative and cholinergic side effects [4446]. Although it
has not been formally tested, trazodone is a usually well-tolerated sedating antidepressant. Hypnotic
drugs such as zolpidem, zoplicone and eszoplicone can also be used, and act mainly through the BZ1
receptor. Benzodiazepines should be used cautiously as they may disrupt sleep architecture.
Sodium oxybate is the sodium salt of gamma-hydroxybutyrate (GHB), an endogenous short chain
fatty acid, used for the oral administration of exogenous GHB [47,48]. The supraphysiological
concentrations induced by exogenous administration probably lead to qualitatively different neuronal
activity from that of endogenous GHB. GHB may play a neuromodulating/neurotransmitting role, and
sodium oxybate is approved by the FDA for the treatment of cataplexy and excessive daytime sleepi-
ness. It has recently also been shown to improve pain and fatigue in phase III FM trials [49].
Thirty percent of FMpatient suffer fromdepression at the time of diagnosis, and 5060% sometimes
during their lifetime [50]. There is also evidence that anxiety can be as common as depression in FM
patients, and post-traumatic stress disorder (PTSD) is more prevalent in FMpatients than in the general
population [51].
The central monoaminergic neurotransmission abnormalities observed in depression may play
a role in FM pathophysiology because dysfunctioning 5-HT- and NE-mediated descending pain-
inhibitory pathways are important mechanisms in FM-related pain. Antidepressants that increase
5-HT- and NE-mediated neurotransmission are frequently used to treat FM and other chronic pain
conditions, particularly neuropathic pain. Inhibiting both 5-HT and NE re-uptake transporters using
TCAs or SNRIs seems to be more effective in treating pain and FM than inhibiting either transporter
alone with selective SSRIs or noradrenergic re-uptake inhibitors (NARIs) [44,52], but the efcacy of
TCAs is counterbalanced by their side effects. SSRIs such as citalopram [53], escitalopram, paroxetine
[54] and sertraline are not effective against pain but. like uoxetine, could be used to treat associated
depression.
Non-pharmacological treatments
Most FM patients complain of severe functional limitations in activities of daily living [55] and,
not surprisingly, are physically deconditioned [5]. Active and passive mobilisation have both been
tried, but recent reviews do not clearly show their efcacy. Active aerobic and anaerobic physical
exercises are pivotal treatments in FM, but patients often nd it difcult to start and maintain
exercise programmes [56,57]. The internet can provide access to many types of physical training
P. Sarzi-Puttini et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 311319 315
and exercises. Moreover, words such as movement or physical exercise are sometimes used
without specifying the type of exercise, its duration, or the intensity of the training. In this respect,
physical exercise is similar to drug because neither are sufcient by themselves: specic details
of the treatment should always be given. A very recent meta-analysis of all studies in the Cochrane
Central Register for Controlled Trials indicates that there is moderate evidence suggesting that
aerobic-only exercise training at American College of Sports Medicine (ACSM)-recommended
intensity levels has positive effects on global well-being and physical function, and a possible effect
on pain and tender points [58]. Strength and exibility are under-evaluated, but strength training
may have a positive effect on FM symptoms. The meta-analysis suggests that aerobic-only training
has benecial effects on physical function and some FM symptoms. However, there is still a lack of
data concerning the long-term efcacy of movement and exercise in controlling the clinical picture.
Aerobic exercises can be performed in a traditional dry environment or in water (deep water
running programmes, hydrokinesis therapy in heated water, and in spas) [59,60]. Generally, both
aerobic and anaerobic exercises are combined with educational and occupational programmes
[6166]. However, although the short-term efcacy of exercise is widely accepted, long-term
compliance seems to be a critical issue as most studies report a lack of persistent effects associated
with a failure to maintain exercise programmes [67].
The passive movements induced by vertebral manipulations, nger pressure on trigger points,
craniosacral manipulation and other forms of chiropractics have been tested. A controlled study of the
efcacy of chiropractics has shown a reduction in pain and disability levels assessed using the Oswestry
Pain Disability Index and the Neck Disability Index but, although positive, these results should be
considered with caution and cannot be generalised (54). The stretch and spray technique is a popular
form of myofascial pain therapy in rehabilitation as it combines the effect of rapid cooling of the
overlying skin using a vapocoolant such as uorimethane with passive muscle elongation. However,
despite its popularity, only one study has reported a reduction in trigger point pain measured by means
of a pressure algometer and VAS in patients with myofascial pain and, to the best of our knowledge,
there have been no studies of its use in FM patients [68].
Combination therapy
In general, about half of all treated patients with medication seem to experience a 30% reduction of
symptoms, suggesting that many patients with FM will require additional therapies [69]. The number
of randomized controlled trials of exercise or behavioral interventions in the FM literature has
increased dramatically in the past decade [70,71]. Progressive walking, simple strength training
movements, stretching activities, aerobic exercise improve functional status, and self-efcacy in
women with FM actively being treated with medication [72]. Thus, other forms of treatment, including
exercise, cognitive behavioural therapies and self-management strategies, may be necessary to achieve
satisfactory treatment outcomes. Surprisingly no controlled randomized data emerge from the liter-
ature which explains how much improvement its possible to get from combining a pharmacological
treatment with a structured rehabilitation or psychological program [73,74]. Multiple medications are
commonly used, often in combination. However, it is important to have knowledge about potential
adverse drug interactions for example the concomitant use of SSRIs and SNRIs or two SNRIs can result
in serotonin syndrome which can be difcult to detect and toxic. If a patient prefers to keep their
medication use to a minimum, it would make sense to choose one or two medicines that can impact
several symptom domains effectively rather than just one [75].
Herbal and nutritional supplements
Authors [76] have reviewed the effects of St. Johns wort, ginseng, valerian, botanical oil, melatonin,
magnesium, dehydroepiandrosterone, NADH, S-adenosylmethionine, growth hormone, chlorella pyr-
enoidosa, 5-hydroxytryptophan, and several dietary supplements. They reported that this herbal and
nutritional supplements showed promising results in early trials, but mixed results are when the
studies become methodologically more sophisticated.
P. Sarzi-Puttini et al. / Best Practice & Research Clinical Rheumatology 25 (2011) 311319 316
Conclusions
It is clear that, as in the case of other disorders, the most efcacious treatment of FM needs to
combine the main elements of pharmacotherapy, exercise, physical therapy and CBT. A number of
medical treatments have been used to treat the various symptoms of FM (pain, sleep disturbances,
anxiety and depression) with the nal aim of improving the patients quality of life. Psychological and
physical therapy may sometimes be more effective than pharmacological treatment. A number of
studies have also evaluated the effect of moderately intense exercise, the level that is most suitable for
usually deconditioned and unt FM patients.
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Research Agenda
To develop new strategies for treating patients on the basis of their predominant symptoms
To determine whether some pharmacological combinations are more useful than
monotherapy
To develop new recommendations for treating and helping FM patients
To promote a Congress and Meeting with the aim of gaining European approval for the FDA
drugs for FM.
Practice points
The effective management of FM is complex and requires a multidisciplinary approach; it has
been shown that an integrated treatment plan including apropriate patient education,
aerobic exercises and cognitive-behavioural therapy can be effective in alleviating symptoms.
The three drugs approved by the American Food and Drug Administration (FDA) can now be
used as the initial main treatment; although still important, the older approaches can be
added later.
The analgesic drug tramadol is benecial in FM but is not formally approved.
Sodium oxybate is approved by the FDA for the treatment of cataplexy and excessive daytime
sleepiness, and it has recently been shown to improve not only sleep, but also FM-related
pain and fatigue.
SSRIs such as escitalopram and paroxetine are not effective against pain but, like uoxetine,
can be used to treat associated depression.
Moderately intense exercise is best suited to usually deconditioned and unt FM patients.
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