Review One year in review 2019: fibromyalgia
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Review
One year in review 2019: fibromyalgia
F. Atzeni1, R. Talotta2, I.F. Masala3, C. Giacomelli4, C. Conversano5,
V. Nucera1, B. Lucchino6, C. Iannuccelli6, M. Di Franco6, L. Bazzichi4
1
Rheumatology Unit, University of Messina; ABSTRACT influence the findings of the EMG (for
2
Clinical Pharmacology and Toxicology, Fibromyalgia is characterised by example, family neural degenerative
University of Milan; chronic pain, fatigue and functional conditions, diabetes mellitus, vitamin
3
Orthopaedic and Trauma Unit,
symptoms. Its aetiopathogenesis is still B-12 deficiency, etc.) 55 FM subjects
Santissima Trinità Hospital, Cagliari;
4
Rheumatology Unit, Department of a matter of debate, but various phar- remained: 29 subjects with “FM only”
Clinical and Experimental Medicine, macological and non-pharmacological and 26 subjects with FM + rheumatoid
University of Pisa; therapies are currently available for its arthritis (“FM + RA”). All subjects also
5
Department of Surgical, Medical treatment. We review the literature con- underwent skin ankle biopsy for the
and Molecular Pathology, Critical Care cerning the most recent findings related determination of the epidermal nerve
Medicine, University of Pisa; to the aetiopathogenesis, diagnosis, fibre (ENFD). Fourteen other subjects,
6
Department of Internal Medicine
clinical aspects and treatment of FM without FM or RA, examined by the
and Medical Specialities, Rheumatology
Unit, Sapienza University of Rome, Italy. published between January 2018 and same electromyograph, were chosen
January 2019. as an EMG/NCS comparison group.
Fabiola Atzeni, MD, PhD
Rossella Talotta, MD, PhD Ninety percent of the “FM only” sub-
Ignazio Francesco Masala, MD Aetiopathogenesis jects generated a demyelinating and/or
Camillo Giacomelli, PhD In the time frame analysed by this re- axonal sensory-motor polyneuropathy,
Ciro Conversano, PhD view, not so many new aetiopathoge- and 63% had SFN (ENFD ≤7 fibres/
Valeria Nucera, MD netic hypotheses for fibromyalgia (FM) mm), suggesting a mixed fibre neuropa-
Bruno Lucchino, PhD have been formulated with respect to thy in most cases. In addition, 61% of
Cristina Iannuccelli, MD, PhD
other years (1). However, the focus of The “FM-only” subjects showed sug-
Manuela di Franco, MD
Laura Bazzichi, MD the researchers in this year was on the gestive EMG of non-myotomial axonal
Please address correspondence to:
phenomena related to neuropathies. In motor denervation of the lower limbs,
Prof. Fabiola Atzeni, 2018, Grayston et al. (2) proposed an most likely a cause of polyneuropathy,
Rheumatology Unit, interesting meta-analysis on the preva- and 41% met the criteria for “possible”
University of Messina, lence of small fibre neuropathy in FM. chronic inflammatory demyelinating
Via C. Valeria 1, The researcher evaluated 935 scientific polyneuropathy (CIDP). Interestingly,
98100 Messina, Italy articles and underlined the prevalence there was little difference in the EMG/
E-mail: atzenifabiola@hotmail.com of small fibre neuropathy (SFN) in 49% NCS findings between the “FM only”
Received and accepted on January 21, of FM patients. This high prevalence of and the “FM+RA” groups, while in the
2019. SFN in FM emphasises the importance comparison group no pathologic find-
Clin exp Rheumatol 2019; 37 (Suppl. 116): of identifying standard methods for the ing was shown, with the only exception
S3-S10. description of this neuropathy and un- of carpal tunnel syndrome. The results
© Copyright Clinical and derstanding the processes leading to the highlighted by the research group show
Experimental Rheumatology 2019.
development of SFN, to achieve better that the electrodiagnostic characteris-
therapeutic and diagnostic strategies. tics of polyneuropathy, muscle dener-
Key words: fibromyalgia
Moreover, Caro et al. (3) studied for vation and CIDP are common in FM.
the first time large fibre involvement in These findings are often seen to coin-
FM. In the past few years, several stud- cide with SFN and are not significantly
ies have pointed to a link between small affected by the presence of RA. These
fibre neuropathy and FM, but in most of results, besides helping to understand
the cases these studies did not evaluate the aetiopathogenesis of FM, can also
possible alterations in the large fibres. be useful for diagnostic purposes.
The researchers included the electro-
myographic findings of 100 consecu- Diagnosis
tive unselected clinical patients that met The diagnosis of FM is still based on
the 1990 ACR criteria for FM. After the patients’ reports and on clinical assess-
exclusion of FM subjects with con- ment, mainly because the pathogenesis
Competing interests: none declared. comitant clinical conditions that could of FM is still not well understood and
Clinical and Experimental Rheumatology 2019 S-3One year in review 2019: fibromyalgia / F. Atzeni et al. because of the lack of reliable biomark- mon medical co-morbidities; dimension the possibility to take into account the ers of the disease. The publication of the 4: neurobiological, psychosocial, and many other associated symptoms that 2010/2011 American College of Rheu- functional consequences; and dimen- may support the diagnosis of FM. This matology (ACR) criteria for the diagno- sion 5: putative neurobiological and could make the FM identification more sis of FM superseded the traditional psychosocial mechanisms, risk factors, practical in clinical settings and at the 1990 ACR classification criteria, ac- and protective factors (8). Recently Ar- same time simplify the identification of cording to the identification of the mul- nold et al., in order to address the prob- FM patients for research purposes (9). ti-symptomatic nature of FM and the lem of the limited reliability and validi- The multidimensional approach to FM difficulty of the standardisation of the ty of the existing diagnostic criteria, definition offers undoubtedly advantag- tender points exam, required in 1990 published a multidimensional diagnos- es in terms of current clinical practice ACR criteria (4). However, subsequent tic framework applied to FM. This is and of diagnosis, but considering the validation studies showed that in spite based on the review of the existing diag- heterogeneity of the disease and the of the simplification of FM diagnosis nostic criteria, it reflects the current un- possible changes during the time of the through the application of symptom derstanding of FM and is thought to be disease features, it may be limiting in scales, such as the widespread pain in- useful in a practical clinical setting. terms of practical management of the dex (WPI) and the symptom severity Identifying FM mainly as a pain disor- single FM patient. Indeed, a recent ret- scale (SSS), there was a substantial mis- der, the core diagnostic criteria (dimen- rospective analysis of a large number of classification mostly of patients with sion 1) include the presence of multisite patients included in an FM continuum severe regional pain disorders (5). The pain, defined as the presence of pain in spectrum, identified 4 possible classes misdiagnosis occurred principally be- 6 out of 9 possible sites together with of the disease. Class 1 was represented cause the 2010/2011 criteria did not moderate to severe fatigue or sleep by a mostly regional FM within the con- consider the spatial distribution of the problems assessed by a health care pro- test of the widespread pain while class 2 painful sites. Therefore, in 2016 a re- fessional. Those must have been present was characterised by a greater severity vised set of criteria was published. This for at least 3 months. Dimension 2, of pain, a broader involvement of body revision introduced “generalised pain namely features that may support a di- regions and several associated symp- criteria”, defined as the presence of pain agnosis of FM, is identified in the ten- toms. These two classes represented the in 4 out of the 5 possible painful body derness to touch (positive tender points most prevalent in the study population, regions, which allowed the exclusion of exam), the dyscognition (trouble con- and their clinical phenotype overlaps the regional pain syndromes from the centrating, forgetfulness, and disorgan- with the one identified by the diagnostic diagnosis of FM without losing the di- ised or slow thinking), musculoskeletal criteria. Class 3 was characterised by an agnostic accuracy of the criteria set (6). stiffness and environmental sensitivity increase in the level of pain compared to Nevertheless, uncertainty and lack of (intolerance to bright lights, loud nois- the previous classes, a strict association confidence in FM diagnostic criteria use es, perfumes and cold). A broad spec- with sleep disorders and to the possibil- in clinical practice is still reported, es- trum of possible comorbidities (dimen- ity of chemical sensitivity. The highest pecially in primary care settings (7). sion 3) has been identified as frequently severity of pain and of associated symp- The Analgesic, Anesthetic, and Addic- associated to FM, which includes sev- toms was present in class 4, which rep- tion Clinical Trial Translations Innova- eral somatic pain disorders, psychiatric resented the “secondary FM” to other tions Opportunities and Networks conditions, sleep disorders and rheu- diseases such as multiple sclerosis and (ACTTION) public-private partnership matic diseases. The outcomes related to lupus, which had a high prevalence in with the U.S. Food and Drug Adminis- the disease, the poor quality of life and this class. During the follow-up, some tration (FDA) and the American Pain the high indirect cost that belong to the patients showed a tendency to progres- Society (APS) in 2013 gathered togeth- burden of FM are described in dimen- sion from the lower to the higher classes er an international working group of cli- sion 4. This last dimension includes the in a fairly linear fashion, although the nicians and basic scientists. The aim of risk factors for the disease, such as fa- progression was also influenced by the the working group was to address the miliarity for functional chronic pain dis- specific comorbidities and the presence problem of the limited reliability and orders and environmental stressors that of secondary conditions. The results of validity of the existing diagnostic crite- may trigger the disease, e.g. early life- this study suggest that FM represents a ria for chronic pain disorders in clinical time adverse events, trauma, medical disease continuum in which the central- practice. Accordingly, the group initiat- conditions and psychosocial stressors, ised pain becomes more centralised as ed the ACTTION-APS Pain Taxonomy together with the current knowledge the disease progresses, and that the (AAPT) initiative, to develop a diag- about the putative pathophysiologic characterisation of how the patients pro- nostic system that would be clinically mechanism that may sustain the disease gress may improve diagnosis and con- useful and consistent across chronic (see Pathogenesis). The AAPT taxo- sequent management (10). Considering pain disorders. The AAPT Taxonomy nomic approach to FM offers a system- all the issues in the current clinical diag- considers 5 dimensions: dimension 1: atic method to diagnose FM, focusing nosis of FM, in the application of diag- core diagnostic criteria; dimension 2: on limited number of core diagnostic nostic criteria and in understanding and common features; dimension 3: com- symptoms but at the same time giving possibly predicting the natural history S-4 Clinical and Experimental Rheumatology 2019
One year in review 2019: fibromyalgia / F. Atzeni et al. of the disease, the lack of a reliable bio- amount of different metabolites in bio- dles in skin biopsy, increased cold and marker is a main unmet need in FM logic fluid to identify the variation of warm detection thresholds in quantita- management. Nonetheless, several new the metabolites contents that can repre- tive sensory testing and nociceptor hy- acquisitions in terms of understanding sent a fingerprint of a specific condi- perexcitability. The study of the small biologic modification of FM patients tion. An interesting approach recently fibre pathology through the skin biopsy have been recently reported and some described involves the metabolomic represents a promising and easily per- of them have the potential for future screening of the low-molecular weight formable diagnostic test that may allow clinical application. In recent years, bio- fraction metabolites of human blood the identification of FM patients with marker research on biological fluid has collected by finger-stick. Using the in- an underlying neuropathy and thereaf- been enriched by the identification of trinsic vibrational pattern of the differ- ter guide the therapeutic choice through relatively new molecules of interest. ent molecules after absorbing infrared drugs that are active on the neuropathic For example, peculiar miRNA profiles light, the authors have been able to suc- aspects of pain. A technique recently on blood, saliva (11) and cerebrospinal cessfully classify FM patients and dis- applied to the successful identification fluid (12) have shown the ability to di- criminate them from patients affected of the small fibre pathology in FM, cor- agnose and characterise FM. However, by systemic lupus erythematosus or neal confocal microscopy, is basically the studied populations were small and rheumatoid arthritis, without misclassi- an in vivo microscopy that may become a validation on larger cohorts is needed. fication. Moreover, the characteristic of a useful and non-invasive FM diagnos- The application of innovative tech- the vibrational spectra of FM patients tic test (18). The “central sensitisation” niques of proteomic or metabolomic correlated with pain severity measured has always been strongly implicated in analysis on the same biological fluids through the revised fibromyalgia im- FM pathophysiology. The neuroim- offers new potentiality in biomarker pact questionnaire (FIQR). Apart from mune activation is one of the potential identification. Studying a large number being a promising diagnostic tool in mechanisms that may be involved in of different proteins in the biological FM, this kind of metabolomic analysis the central nervous system abnormality fluid gives the possibility to combine may be useful to identify serum metab- described in FM. Recently, a combined more proteins of interest and increase olites that could be valuable as bio- research group from Sweden and the diagnostic accuracy. A proteomic analy- markers. In fact, the discriminating re- United States demonstrated for the first sis of whole saliva performed on FM gion of the vibrational spectra was time the presence of activated glia, and patients, compared with healthy con- dominated by bands characteristics of consequently of active neuroinflamma- trols, patients with migraine and pa- pyridine ring, tyrosine residues in pro- tion in the brain of FM patients. Using tients with rheumatoid arthritis, showed teins and protein backbone, highlight- positron emission tomography (PET) an increased expression of several pro- ing the importance of aromatic and car- imaging and radioligands that bind to teins like serotransferrin, alpha-enolase, boxylic acid molecules as potential bio- the 18-kDa translocator protein (TSPO), phosphoglycerate-mutase-I and trans- markers, including tryptophan and its the authors described an increased up- aldolase. Performing a ROC curve metabolites (15). The role of tryptophan take of the radioligand in FM patients’ analysis, the combination of apha-eno- and its metabolite, serotonin, in FM brain, especially in the brain regions lase, phosphoglycerate-mutase-I and pathogenesis has been supported by a previously implicated in FM pathology. serotransferrin obtained a good dis- number of experimental observations TSPO expression is normally low in criminative ability (AUC 0.792) (13). and confirmed by the common use in healthy brain tissue but is dramatically Similarly, a proteomic analysis per- FM treatment of selective serotonin upregulated in activated glial cells un- formed on plasma of FM patients iden- reuptake inhibitors (16). A reduced lev- der inflammatory stimuli. Moreover, tified 33 differently expressed proteins el of serum serotonin in blood sample the radioligand uptake in several brain belonging to several patterns like acute- of women recently diagnosed with FM regions correlated significantly with the phase reaction, Liver-X Receptor/Reti- compared to controls has been reported. subjective fatigue score reported by FM noid-X Receptor activation, Farnesoid- However, there was no relation between patients. Because it suggests a possible X Receptor/Retinoid-X Receptor acti- the reduction of serum serotonin and association between neuroinflamma- vation, complement and coagulation, clinical manifestation, suggesting a tion and FM, this work opens to future suggesting the existence of a plasmatic possible use of serotonin levels in FM researches about the role taken by acti- inflammatory protein signature in FM, diagnosis but not in the assessment of vated microglia in FM with the possible which may be related to a neuroinflam- the disease severity (17). The investiga- identification of diagnostic biomarkers matory process. Among the proteins tion of neurologic abnormalities both in or therapeutic strategies (19). Unfortu- that presented an increased serum level the peripheral and central nervous sys- nately, to date, none of these diagnostic in FM patients, haptoglobin and fibrin- tem have been a rich field of research in tests is sufficiently validated to be intro- ogen had the highest FM/control ratio, FM. Several different groups have de- duced into clinical practice. Further representing two interesting possible scribed the presence of a small fibre studies are needed in order to identify targets of further study on their role as neuropathy in a large number of FM the best diagnostic test that can easily biomarkers (14). As well as proteomics, patients, represented by a reduction in help the diagnosis and management of metabolomics aims to screen a large dermal unmyelinated nerve fibre bun- FM patients. Clinical and Experimental Rheumatology 2019 S-5
One year in review 2019: fibromyalgia / F. Atzeni et al.
Treatment drug mirtazapine is a central presyn- prescription in a wide set of chronic
Due to the heterogeneity of symptoms aptic α2 adrenergic antagonist with pain diseases, including FM, although
and the poorly known pathogenesis, serotonergic and noradrenergic effects, the real effects on symptom relief are
the therapy of fibromyalgia (FM) still acting on amygdala, hippocampus, inconclusive (25). However, in an
remains a challenge for physicians. Ac- frontostriatal circuits, cortical midline 8-week prospective, single centre fea-
cording to the most recent European structures and parietal cortex. This drug sibility study, the combined treatment
League Against Rheumatism (EULAR) increases neuronal response to positive with gabapentin 900 mg/daily plus
guidelines, once the diagnosis of FM emotional and reward boosts, and at- osteopathic manipulative medicine re-
is made, priority should be given to tenuates the processing of threatening sulted in improved Wong-Baker FAC-
non-pharmacologic treatment (20). The stimuli (21). In addition, mirtazapine ES Pain Rating Scale scores, although
reason lies in cost-effectiveness, pa- contrasts the effects of histamine on the Fibromyalgia Impact Questionnaire
tient’s preference, safety and availabil- H1 receptors and this confers sedative (FIQ) score and the number of tender
ity. Physical exercise, having the best properties that may be exploited in the points did not change significantly
profile of efficacy and safety, should be treatment of sleep disorders. A recent from baseline (26).
prescribed to every patient with a diag- systematic review aimed to evaluate the A novel drug, acting as a N-methyl-d-
nosis of FM. The efficacy of pharma- effects of mirtazapine in FM patients aspartate (NMDA) receptor modulator
cologic intervention has a weak level (22). Data from selected articles (three and known as NYX-2925, is currently
of evidence, and, due to potential side randomised placebo-controlled trials investigated in FM patients in a phase
effects and low compliance, should be and one open-label trial) reported an 2 clinical trial (NCT03249103, www.
indicated in specific cases (e.g. unre- improvement in pain, sleep and qual- clinicaltrials.gov). The rationale for the
sponsive pain or sleep disturbances). ity of life, despite different treatment use of this agent lies in the role played
In the most severe situations, patients doses and duration. Another systematic in neuronal plasticity as well as in the
could benefit from a multimodal thera- review by the Cochrane group on the control of learning and memory pro-
peutic approach. use of mirtazapine in FM evaluated the cesses, and in the promising results ob-
efficacy versus placebo in pain relief, served in analgesia in preclinical stud-
Pharmacological therapies patient’s perception of efficacy, safety ies (27).
The therapeutic management of FM in- and tolerability (23). The analysis of Mexiletine is an anti-arrhythmic drug
cludes the use of drugs modulating neu- data from 3 low-quality studies on that blocks in a non-selective way the
rotransmission and acting on the pain, more than 500 FM patients treated for voltage-gated sodium channels. The
emotional and reward circuits. Recent at least 7 weeks revealed modest effica- drug has also modulatory effects on
European guidelines provided a de- cy of mirtazapine over placebo in pain chronic nociception and muscle stiff-
tailed list of recommended therapies ac- relief and Patient Global Impression ness. The retention rate and side effects
cording to a review of published meta- of Change (PGIC), but also reported a of mexiletine in neuropathic pain and
analyses and systematic reviews (20). higher incidence of adverse events in FM patients was evaluated in a retro-
The authors evaluated the efficacy and the mirtazapine arm, including somno- spective cohort study (28). Mexile-
safety profile of several drugs, includ- lence, increase in serum transaminases tine was prescribed at daily dosage of
ing antidepressants, pain modulators, and weight gain. 150 up to 450 mg to 21 FM patients.
hormones, anticonvulsants and muscle The serotonin and norepinephrine About 30% of patients discontinued the
relaxants. For some of them, including reuptake inhibitor antidepressant mil- treatment at 6 and 12 months, mainly
amitriptyline, pregabalin and dulox- nacepram was tested in a prospective, because of gastrointestinal, neurologic
etine, encouraging results on pain have randomised, controlled double-blind and cardiac events. Although not re-
been reported. Other symptoms, such as clinical trial in patients with FM (24). ported in this study, the risk of serious
sleep disturbance, fatigue and disability, The researchers evaluated the effects side effects, such as QT abnormali-
may ameliorate at a different rate under of milnacipram titrated up to 100 mg/ ties and torsades de pointes, limits the
amitriptyline, pregabalin or serotonin- daily in a group of 54 FM patients who widespread use of this treatment in FM
ergic agents. On the contrary, based on were randomised to receive the active patients.
the disadvantageous profile of efficacy compound or placebo. After 1 month The use of cannabinoids for the manage-
and safety, the use of other compounds, of treatment, no significant difference ment of FM has been diffuse in recent
such as cyclobenzaprine, growth hor- emerged between the two arms accord- years and some studies evidenced that
mone, non-steroideal anti-inflamma- ing to conditioned pain modulation, it could add some benefits in the con-
tory drugs (NSAIDs), steroids, strong global pain, mechanical and thermal trol of accessorial symptoms, including
opioids and monoamino oxidase inhibi- thresholds, allodynia, cognition, and chronic low-back pain (29). Cannabi-
tors has been discouraged. Further evi- tolerance. noids derive from the plant Cannabis
dences on the effects of other molecules The off-label use of gabapentin, a sativa L. and exert their effects by inter-
on FM symptoms emerged from small γ-aminobutyric acid (GABA)-mimet- acting with the cannabinoid type 1 re-
trials or additional reviews conduced in ic drug, has given rise to noteworthy ceptor (CB1-R) expressed by neuronal
the last 12 months. The antidepressant interest in the last few years, due to cells and cannabinoid type 2 receptor
S-6 Clinical and Experimental Rheumatology 2019One year in review 2019: fibromyalgia / F. Atzeni et al. (CB2-R) present on cells from the im- systematic review evaluated the effica- (37). When applied to the symptom mune system. Cannabis contains vari- cy (intended as a 30% or 50% improve- insomnia, an 8-week CBT has shown ous amounts of psychoactive compo- ment of pain from baseline and PGIC to rescue grey matter atrophy observed nents, including the ∆9- tetrahydrocan- amelioration) and safety of drug com- through magnetic resonance imaging nabinol (THC), which modulates noci- bination versus mono-therapy or place- (MRI) in FM patients (38). Several ception, cognition and motor function bo in published randomised controlled studies have demonstrated, in fact, that by binding CB1-R, and cannabidiol trials on FM patients (34). The authors long-lasting insomnia may reduce the (CBD) which acts as a CB2-R antago- selected 16 studies enrolling 1,474 pa- volume of the hippocampus, amyg- nist and a 5-hydroxytryptamine (5-HT) tients. The most frequent combinations dala, anterior cingulate cortex, insula, receptor agonist, modulating mood and of drugs included the association of medial frontal cortex, parahippocam- cognition. Due to the different phar- NSAIDs with benzodiazepine, amitrip- pus, pre-frontal cortex, and thalamus. macodynamics of THC and CBD, a tyline with fluoxetine, tramadol with When added to relaxation, GrpMI in- recent randomised placebo-controlled paracetamol, and monoamine oxidase tervention similarly showed beneficial 4-way crossover trial aimed to evaluate inhibitor with 5-hydroxytryptophan. effects on mood and pain sensitisation the efficacy of 3 inhaled cannabinoids, The combination of drugs seemed to in 56 FM women enrolled in a 12-week having a different chemical composi- give a greater advantage on pain than a randomised trial (39). tion, versus placebo for the treatment single treatment alone, with only mild Due to the chronicity of the disease, of FM (30). These drugs (Bedrocan®, side effects reported. However, the re- one of the main concerns in treating Bediol® and Bedrolite®) differ, in fact, sults were biased by the heterogeneity FM patients is the poor compliance for the CBD/THC ratio. Testing 20 FM of the study designs and variability in to a long-lasting treatment. Psycho- patients, the authors evidenced a small sample sizes. logical support given by means of an analgesic effect after a single inhala- Internet platform proved to be an ef- tion of each compound; interestingly, Non-pharmacological therapies ficacious remedy for FM symptoms, CBD and THC shared synergistic phar- The non-pharmacological management including pain, fatigue and mood dis- macokinetics, whereas contrasted ac- of FM has been focused on in many orders. A randomised controlled trial cording to pharmacodynamics and an- studies and seems to have a stronger on 140 FM patients assigned or not to algesic effects when co-administrated. impact on clinical manifestations, Internet-delivered exposure showed Bediol®, which has the highest content symptoms and quality of life than the significant advantages on FM symp- of CBD, had the most impactful effect pharmacologic treatment. Novel psy- toms and a high retention rate (94% on mechanic-induced pain. chological support therapy showing of patients in therapy at 12-months) Other data from a meta-analysis con- promising results in FM includes virtu- (40). In addition, this strategy showed ducted on patients treated with cannabi- al reality, Basic Body Awareness Ther- greater cost-effectiveness than no treat- noids for non-oncologic chronic pain, apy (BBAT), Cognitive-Behaviour ment, concerning both direct and indi- including subjects suffering from FM- Therapy (CBT) and Group Music and rect costs in those patients achieving related pain, evidenced no superiority Imagery (GrpMI) intervention. Virtual positive results (41). Results on the of cannabinoids over placebo in terms reality modulates pain perception by in- efficacy of Internet-delivered therapy of physical or emotional functioning, fluencing attention, concentration and from 6 randomised controlled trials on whereas low-quality evidence on the emotions. Therefore, acting through a 493 FM patients were reviewed by a improvement of sleep and PGIC was mechanism that does not directly in- recent meta-analysis (42). The authors reported (31). volve the nociceptive pathway, virtual demonstrated a significant reduction in The use of opioids in FM has shown reality may represent a valid additional mood disturbances and disability at 6 delusive results (32), although trama- tool to pharmacologic prescription in months, despite no benefit in terms of dol seems to moderately reduce pain chronic pain conditions, like FM (35). ≥50% pain relief was observed com- (20). Naltrexone, an opioid antagonist, BBAT is a movement awareness train- paring Internet-derived psychological has achieved promising results in FM- ing programme that teaches patients therapy to waiting list. Another sys- related pain due to the increase in the how to correctly move in space and tematic review on Internet-delivered endorphinergic tone related to the tran- time, increasing awareness of body co- cognitive behaviour therapy in patients sient blockade of opioid receptors in ordination. In a randomised study, 20 with chronic diseases, including FM, the central nervous system; and some FM patients assigned to BBAT and fol- showed the greatest effect in anxiety pilot studies evidenced a good profile lowed-up for 24 weeks showed a sig- and depression symptom modulation of efficacy and safety of this drug in the nificant reduction in pain and anxiety (43). In the near future, the implemen- FM setting (33). scale scores compared to 21 controls tation of mobile applications delivering Due to the great variability in clinical (36). CBT focuses on coping strate- self-administered cognitive behaviour- expression, FM often requires com- gies, emotional control and cognitive al treatment may further enhance the bined therapeutic strategies, including psychology and has shown success- adherence of patients to non-pharma- both pharmacologic and non-pharma- ful results in counteracting mood dis- cologic therapeutic programmes (44). cologic approaches. A recent Cochrane orders and disability of FM patients Physical exercise is a cornerstone in Clinical and Experimental Rheumatology 2019 S-7
One year in review 2019: fibromyalgia / F. Atzeni et al. the non-pharmacologic management mud-bathing for a month, a benefit has cle tender points, in a randomised clini- of FM, however, specific interventions been registered in pain sensitisation to- cal trial, showed a significant improve- and programmes are poorly defined gether with an amelioration of serum ment of pain from baseline in FM-re- (45). A number of studies reported a biochemical parameters such as tri- lated facial muscle tenderness, achiev- significant benefit of the Chinese dis- glycerides and C-reactive protein (52). ing similar results to the local injection cipline Tai Chi over aerobic exercise in The mechanical, chemical and ther- of lidocaine 2%, which, however, rep- terms of mood and sleep disturbance, mal properties of balneotherapy seem, resents an invasive tool of pain control disability and quality of life (46, 47). in fact, to alleviate pain by means of (58). The use of weak magnetic field (2 However, physical activity does not several mechanisms. In particular, an Tesla) to induce neuro-modulation in seem to influence pain sensitivity, the increase has been observed in pain the left dorsolateral prefrontal cortex, a management of which should require threshold mediated by the activation of brain area crucial for pain sensitisation, the addition of a pharmacologic inter- the descending inhibitory pain system has been tested in a 4-week randomised vention or other non-pharmacologic and gamma-fibres and augmented lev- double blind placebo-controlled trial approaches (48). els of beta-endorphin, growth hormone on 26 participants with a diagnosis of Both hot and cold temperature can and adrenocorticotropic hormone in FM, showing a significant improve- modulate nociception by acting on opi- FM patients undergoing balneother- ment in the symptom fatigue (59). The oid endogenous pain inhibitory system apy (53). In a randomised controlled results from a comparative study on and specific alternation of rhythm in 6-month trial, 100 patients with FM 120 FM patients evidenced the supe- temperature (SART) stress can impair were assigned to highly mineralised riority of repetitive transcranial mag- the control of nociceptive stimuli in sulphate water or tap water. VAS pain netic stimulation over regenerative rats (49). Some studies on the effects of and FIQ significantly ameliorated in injection therapy, such as prolotherapy, both cold and hot temperature exposure patients assigned to the first arm of in Beck Depression Inventory (BDI) have been carried out in FM patients. treatment at day 15th and benefits were scores and cortical functions, whereas Cryotherapy is widely used in sport maintained over the follow-up period pain was less controlled (60). The tech- medicine due to the anti-inflammatory, (54). The application of muscle exer- nique is not invasive and is well toler- anti-oedema and analgesic properties. cise (e.g. using the Tai Chi technique) ated with site discomfort and headache In a study involving 60 FM participants in a warm water context, namely the reported as the most common side ef- randomly assigned to whole body cryo- aquatic Ai-Chi programme, can repre- fects. In addition, the recent production therapy or rest, the researchers showed sent a further tool to control pain and of portable devices for home use could reduced FIQ, visual analogic scale ameliorate quality of life, as shown significantly ameliorate compliance to (VAS) for pain and Combined Index by the results of an experimental pilot this kind of therapy (61). of Severity of Fibromyalgia (ICAF) study on 20 FM subjects (55). Finally, some studies have reported scores in treated patients (50). How- The use of transcutaneous and percu- that dietary changes may have a posi- ever, side effects were recorded, some taneous electrical nerve stimulation, tive repercussion on muscular pain. of which, including palpitations, mus- laser therapy and pulsed electro-mag- FM subjects often have a deficit in se- cle stiffness, tremor, sleep disturbance netic fields has also been experimented lenium, magnesium, zinc, vitamins B and headache, could have represented a in FM subjects. A 12-week randomised and D and proteins, and may benefit disease flare. Since the pharmacologic controlled trial on 108 FM women aim- from the intake of carnitine, anti-oxi- background of the examined cohort is ing to investigate the analgesic effects dants, lactose-free and low-histamine not detailed, it may be hypothesised of the use of a Bio-Electro-Magnetic- food and aromatic amino acids (62). that the combination of cryotherapy Energy-Regulation (BEMER) device These nutrients can reduce systemic plus tranquilliser or muscle-relaxant did not find any significant difference and neuronal inflammation and restore agents would have improved the final compared to women assigned to a muscle strength. In addition, aromatic result and avoided some of the report- sham device (56). Electro-magnetic amino acids, like tryptophan, may ed side effects. Another randomised fields seem to act by increasing micro- normalise the level of neurotransmit- trial involving 24 FM patients, part of circulation and restoring the function ters associated to sleep and mood con- whom were assigned to a whole body of the immune cells, however the exact trol. The addition of vitamin D 50,000 cryotherapy group for a total of 10 ses- role in FM is uncertain. Similarly, the IU weekly to trazodone 25 mg a day sions over a period of 8 days, reported use of low-level laser therapy added showed a significant improvement in better scores in the Medical Outcome to functional exercise failed to demon- quality of life and pain perception in a Study Short Form-36 questionnaire, strate superiority to exercise alone in cohort of vitamin D-deficient FM pa- evidencing an improvement in the pain, muscle performance, mood dis- tients followed up for 8 weeks (63). quality of life (51). On the other hand, orders and quality of life in a double- According to another recent study, due to muscle relaxation, the applica- blind randomised clinical trial on 22 the combination of a lacto-vegetarian tion of heat has given beneficial effects FM women (57). diet with exercise seems to represent a in FM patients. In a study involving On the contrary, the application of 12 more powerful means of pain control 7 FM patients daily undergoing 40°C sessions of laser therapy on facial mus- and muscle strengthening (64). S-8 Clinical and Experimental Rheumatology 2019
One year in review 2019: fibromyalgia / F. Atzeni et al.
To conclude, given the wide range of M: Circulating microRNA profiles as liquid d-Aspartate Receptor Modulator that Induces
biopsies for the characterization and diagno- Rapid and Long-Lasting Analgesia in Rat
non-pharmacologic therapies avail-
sis of fibromyalgia syndrome. Mol Neurobiol Models of Neuropathic Pain. J Pharmacol
able and showing promising results in 2017; 54: 7129-36. Exp Ther 2018; 366: 485-97.
FM, physicians should be able to tai- 12. BJERSING JL, LUNDBORG C, BOKAREWA 28. ROMMAN A, SALAMA-HANNA J, DWIVEDI
lor the treatment to the most prevalent MI, MANNERKORPI K: Profile of cerebrospi- S: Mexiletine usage in a chronic pain clinic:
nal microRNAs in fibromyalgia. PLoS One indications, tolerability, and side effects.
FM manifestations (pain, sleep distur- 2013; 8: e78762. Pain Physician 2018; 21: E573-E579.
bances, mood disorders, somatic symp- 13. CIREGIA F, GIACOMELLI C, GIUSTI L et al.: 29. YASSIN M, ORON A, ROBINSON D: Effect of
toms). Moreover, in the near future, the ”Putative salivary biomarkers useful to dif- adding medical cannabis to analgesic treat-
possibility to deliver psychological or ferentiate patients with fibromyalgia. J Prot- ment in patients with low back pain related
eomics 2019; 190: 44-54. to fibromyalgia: an observational cross-over
physical therapy directly at home by 14. RAMÍREZ-TEJERO JA, MARTÍNEZ-LARA single centre study. Clin Exp Rheumatol
means of a portable device or internet- E, RUS A, CAMACHO MV, DEL MORAL ML, 2019; 37 (Suppl. 116): S13-S20.
based platforms could significantly in- SILES E: Insight into the biological pathways 30. van de DONK T, NIESTERS M, KOWAL MA,
crease the adherence to treatment and underlying fibromyalgia by a proteomic ap- OLOFSEN E, DAHAN A, van VELZEN M: An
proach. J Proteomics 2018; 186: 47-55. experimental randomized study on the anal-
reduce direct and indirect costs. 15. HACKSHAW KV, AYKAS DP, SIGURDSON GT gesic effects of pharmaceutical-grade canna-
et al: Metabolic fingerprinting for diagnosis bis in chronic pain patients with fibromyal-
References of fibromyalgia and other rheumatologic dis- gia. Pain 2018 Dec 20.
1. TALOTTA R, BAZZICHI L, DI FRANCO M et orders. J Biol Chem 2018 Dec 6. 31. STOCKINGS E, CAMPBELL G, HALL WD et
al.: One year in review 2017: fibromyalgia. 16. WALITT B, URRÚTIA G, NISHISHINYA MB, al.: Cannabis and cannabinoids for the treat-
Clin Exp Rheumatol 2017; 35 (Suppl. 105): CANTRELL SE, HÄUSER W: Selective seroto- ment of people with chronic non-cancer pain
S6-12. nin reuptake inhibitors for fibromyalgia syn- conditions: a systematic review and meta-
2. GRAYSTON R, CZANNER G, ELHADD K et al.: drome. Cochrane Database Syst Rev 2015; analysis of controlled and observa-tional
A systematic review and meta-analysis of the 6: CD011735. studies. Pain 2018; 159: 1932-54.
prevalence of small fiber pathology in fibro- 17. Al-NIMER MSM, MOHAMMAD TAM, ALSAK- 32. GOLDENBERG DL, CLAUW DJ, PALMER RE,
myalgia: Implications for a new paradigm in ENI RA: Serum levels of serotonin as a bio- CLAIR AG: Opioid Use in Fibromyalgia: A
fibromyalgia etiopathogenesis. Semin Arthri- marker of newly diagnosed fibromyalgia in Cautionary Tale. Mayo Clin Proc 2016; 91:
tis Rheum 2018 Aug 23. women: Its relation to the platelet indices. J 640-8.
3. CARO XJ, GALBRAITH RG, WINTER EF: Res Med Sci 2018; 23: 71. 33. METYAS S, CHEN CL, YETER K, SOLYMAN J,
Evidence of peripheral large nerve involve- 18. MARTÍNEZ-LAVÍN M: Fibromyalgia and ARKFELD DG: Low Dose Naltrexone in the
ment in fibromyalgia: a retrospective review small fiber neuropathy: the plot thickens! Treatment of Fibromyalgia. Curr Rheumatol
of EMG and nerve conduction findings in 55 Clin Rheumatol 2018; 37: 3167-71. Rev 2018; 14: 177-80.
FM subjects. Eur J Rheumatol 2018; 5: 104- 19. ALBRECHT DS, FORSBERG A, SANDSTRÖM 34. THORPE J, SHUM B, MOORE RA, WIFFEN PJ,
10. A et al.: Brain glial activation in fibromyalgia GILRON I: Combination pharmacotherapy
4. WOLFE F, CLAUW DJ, FitzCHARLES MA et – A multi-site positron emission tomography for the treatment of fibromyalgia in adults.
al.: The American College of Rheumatology investigation. Brain Behav Immun 2019; 75: Cochrane Database Syst Rev 2018; 2:
preliminary diagnostic criteria for fibromyal- 72-83. CD010585.
gia and measurement of symptom severity. 20. MacFARLANE GJ, KRONISCH C, DEAN LE et 35. POURMAND A, DAVIS S, MARCHAK A, WHI-
Arthritis Care Res 2010; 62: 600-10. al.: EULAR revised recommendations for TESIDE T, SIKKA N: Virtual Reality as a Clin-
5. MÜLLER V, EGLE UT, KOKINOGENIS G, the management of fibromyalgia. Ann Rheum ical Tool for Pain Management. Curr Pain
LEDERBOGEN S, DURRER B, STAUBER S: Dis 2017; 76: 318-28. Headache Rep 2018; 22: 53.
Implications of proposed fibromyalgia crite- 21. KOMULAINEN E, GLEREAN E, MESKANEN K 36. BRAVO C, SKJAERVEN LH, ESPART A, GUI-
ria across other functional pain syndromes. et al.: Single dose of mirtazapine modulates TARD SEIN-ECHALUCE L, CATALAN-MATA-
Scand J Rheumatol 2015; 44: 416-24. whole-brain func-tional connectivity during MOROS D: Basic Body Awareness Therapy
6. WOLFE F, CLAUW DJ, FitzCHARLES MA et emotional narrative processing. Psychiatry in patients suffering from fibromyalgia: A
al.: 2016 Revisions to the 2010/2011 fibro- Res Neuroimaging 2017; 263: 61-9. randomized clinical trial. Physiother Theory
myalgia diagnostic criteria. Semin Arthritis 22. OTTMAN AA, WARNER CB, BROWN JN: The Pract 2018.
Rheum 2016; 46: 319-29. role of mirtazapine in patients with fibromy- 37. KASHIKAR-ZUCK S, BLACK WR, PFEIFFER
7. HADKER N, GARY S, CHANDRAN AB, CREAN algia: a systematic review. Rheumatol Int M et al.: Pilot randomized trial of integrated
SM, McNETT M, SILVERMAN SL: Primary 2018; 38: 2217-24. cognitive-behavioral therapy and neuro-
care physicians’ perceptions of the chal- 23. WELSCH P, BERNARDY K, DERRY S, MOORE muscular training for juvenile fibromyalgia:
lenges and barriers in the timely diagnosis, RA, HÄUSER W: Mirtazapine for fibromyal- The FIT Teens Program. J Pain 2018; 19:
treatment and management of fibromyalgia. gia in adults. Cochrane Database Syst Rev 1049-62.
Pain Res Manag 2011; 16: 440-4. 2018; 8: CD012708. 38. McCRAE CS, MUNDT JM, CURTIS AF et al.:
8. FILLINGIM RB, BRUEHL S, DWORKIN RH et 24. PICKERING G, MACIAN N, DELAGE N et Gray matter changes following cognitive be-
al.: The ACTTION-American Pain Society al.: Milnacipran poorly modulates pain in havioral therapy for patients with comorbid
Pain Taxonomy (AAPT): an evidence-based patients suffering from fibromyalgia: a ran- fibromyalgia and insomnia: a pilot Study. J
and multidimensional approach to classify- domized double-blind controlled study. Drug Clin Sleep Med 2018; 14: 1595-603.
ing chronic pain conditions. J Pain 2014; 15: Des Devel Ther 2018; 12: 2485-96. 39. TORRES E, PEDERSEN IN, PÉREZ-FERNÁN-
241-9. 25. PECKHAM AM, EVOY KE, OCHS L, COVVEY DEZ JI: Randomized Trial of a Group Music
9. ARNOLD LM, BENNETT RM, CROFFORD LJ JR: Gabapentin for Off-Label Use: Evidence- and Imagery Method (GrpMI) for Women
et al.: AAPT Diagnostic Criteria for Fibro- Based or Cause for Concern? Subst Abuse with Fibromyalgia. J Music Ther 2018; 55:
myalgia. J Pain 2018. 2018; 12: 117. 186-220.
10. DAVIS F, GOSTINE M, ROBERTS B, RISKO R, 26. MARSKE C, BERNARD N, PALACIOS A et 40. HEDMAN-LAGERLÖF M, HEDMAN-LAGER-
CAPPELLERI JC, SADOSKY A: Characterizing al.: Fibromyalgia with Gabapentin and Os- LÖF E, AXELSSON E et al.: Internet-Deliv-
classes of fibromyalgia within the continuum teopathic Manipulative Medicine: A Pilot ered Exposure Therapy for Fibromyalgia: A
of central sensitization syndrome. J Pain Res Study. J Altern Complement Med 2018; 24: Randomized Controlled Trial. Clin J Pain
2018; 11: 2551-60. 395-402. 2018; 34: 532-42.
11. MASOTTI A, BALDASSARRE A, GUZZO MP, 27. GHOREISHI-HAACK N, PRIEBE JM, AGUADO 41. HEDMAN-LAGERLÖF M, HEDMAN-LAGER-
IANNUCCELLI C, BARBATO C, DI FRANCO JD et al.: NYX-2925 Is a Novel N-Methyl- LÖF E, LJÓTSSON B, WICKSELL RK, FLINK I,
Clinical and Experimental Rheumatology 2019 S-9One year in review 2019: fibromyalgia / F. Atzeni et al.
ANDERSSON E: Cost-effectiveness and cost- ature-stressed rats. Eur J Pharmacol 2016; trial. Lasers Med Sci 2018 Jun 21.
utility of internet-delivered exposure therapy 784: 61-8. 58. de SOUZA RC, de SOUSA ET, SCUDINE KG et
for fibromyalgia: results from a randomized, 50. RIVERA J, TERCERO MJ, SALAS JS, GIMENO al.: Low-level laser therapy and anesthetic
controlled trial. J Pain 2019; 20: 47-59. JH, ALEJO JS: The effect of cryotherapy on infiltration for orofacial pain in pa-tients
42. BERNARDY K, KLOSE P, WELSCH P, HÄUSER fibromyal-gia: a randomised clinical trial with fibromyalgia: a randomized clinical
W: Efficacy, acceptability and safety of In- carried out in a cryosauna cabin. Rheumatol trial. Med Oral Patol Oral Cir Bucal 2018;
ternet-delivered psychological therapies for Int 2018; 38: 2243-50. 23: e65-e71.
fibromyalgia syndrome: A systematic review 51. VITENET M, TUBEZ F, MARREIRO A et al.: 59. FITZGIBBON BM, HOY KE, KNOX LA et al.:
and meta-analysis of randomized controlled Effect of whole body cryotherapy interven- Evidence for the improvement of fatigue in
trials. Eur J Pain 2019; 23: 3-14. tions on health-related quality of life in fibro- fibromyalgia: A 4-week left dorsolateral pre-
43. MEHTA S, PEYNENBURG VA, HADJISTAV- myalgia patients: A randomized controlled frontal cortex repetitive transcranial magnet-
ROPOULOS HD: Internet-delivered cognitive trial. Complement Ther Med 2018; 36: 6-8. ic stimulation randomized-controlled trial.
behaviour therapy for chronic health condi- 52. MAEDA T, KUDO Y, HORIUCHI T, MAKINO N: Eur J Pain 2018; 22: 1255-67.
tions: a systematic review and meta-analysis. Clinical and anti-aging effect of mud-bathing 60. ABD ELGHANY SE, AL ASHKAR DS, EL-
J Behav Med 2018 Nov 1. ther-apy for patients with fibromyalgia. Mol BARBARY AM et al.: Regenerative injection
44. de la VEGA R, ROSET R, GALÁN S, MIRÓ J: Cell Biochem 2018; 444: 87-92. therapy and repetitive transcranial magnetic
FIBROLINE: A mobile app for improving the 53. GUIDELLI GM, TENTI S, DE NOBILI E, FIO- stimulation in primary fibromyalgia treat-
quality of life of young people with fibromy- RAVANTI A: Fibromyalgia syndrome and spa ment: A comparative study. J Back Musculo-
algia. J Health Psychol 2018; 23: 67-78. therapy: myth or reality? Clin Med Insights skelet Rehabil 2018 Aug 17.
45. ÁLVAREZ-GALLARDO IC, BIDONDE J, Arthritis Musculoskelet Disord 2012; 5: 19- 61. CARVALHO F, BRIETZKE AP, GASPARIN A et
BUSCH A et al.: Therapeutic validity of exer- 26. al.: Home-Based Transcranial Direct Cur-
cise inter-ventions in the management of fi- 54. FIORAVANTI A, MANICA P, BORTOLOTTI rent Stimulation Device Development: An
bromyalgia. J Sports Med Phys Fitness 2018 R, CEVENINI G, TENTI S, PAOLAZZI G: Is Updated Protocol Used at Home in Healthy
Oct 1. balneotherapy effective for fibromyalgia? Subjects and Fibromyalgia Patients. J Vis
46. WANG C, SCHMID CH, FIELDING RA et al.: Results from a 6-month double-blind rand- Exp 2018.
Effect of tai chi versus aerobic exercise for omized clinical trial. Clin Rheumatol 2018; 62. BJØRKLUND G, DADAR M, CHIRUMBOLO S,
fibromyalgia: comparative effectiveness ran- 37: 2203-12. AASETH J: Fibromyalgia and nutrition: Ther-
domized controlled trial. BMJ 2018; 360: 55. PÉREZ DE LA CRUZ S, LAMBECK J: A new apeutic possibilities? Biomed Pharmacother
k851. approach towards improved quality of life in 2018; 103: 531-8.
47. OSTROVSKY DA: Tai Chi may be More Ef- fibromyalgia: a pilot study on the effects of 63. MIRZAEI A, ZABIHIYEGANEH M, JAHED SA,
fective for Improving Fibromyalgia Symp- an aquatic Ai Chi program. Int J Rheum Dis KHIABANI E, NOJOMI M, GHAFFARI S: Ef-
toms Than Aerobic Exercise. Explore (NY) 2018; 21: 1525-32. fects of vitamin D optimization on quality
2018; 14: 391-92. 56. MULTANEN J, HÄKKINEN A, HEIKKINEN P, of life of patients with fibromyalgia: A ran-
48. MERRIWETHER EN, FREY-LAW LA, RAKEL KAUTIAINEN H, MUSTALAMPI S, YLINEN J: domized controlled trial. Med J Islam Repub
BA et al.: Physical activity is related to func- Pulsed electro-magnetic field therapy in the Iran 2018; 32: 29.
tion and fatigue but not pain in women with treatment of pain and other symptoms in fi- 64. MARTÍNEZ-RODRÍGUEZ A, LEYVA-VELA B,
fibromyalgia: baseline analyses from the bromyalgia: A randomized controlled study. MARTÍNEZ-GARCÍA A, NADAL-NICOLÁS Y:
Fibromyalgia Activity Study with TENS Bioelectromagnetics 2018; 39: 405-13. [Effects of lacto-vegetarian diet and stabili-
(FAST). Arthritis Res Ther 2018; 20: 199. 57. GERMANO MACIEL D, TRAJANO DA SILVA zation core exercises on body composition
49. ITOMI Y, TSUKIMI Y, KAWAMURA T: Im- M et al.: Low-level laser therapy combined and pain in women with fibromyalgia: rand-
paired diffuse noxious inhibitory controls to functional ex-ercise on treatment of fibro- omized controlled trial]. Nutr Hosp 2018; 35:
in specific al-ternation of rhythm in temper- myalgia: a double-blind randomized clinical 392-9.
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