1813 01 reuma3 editoriale

Reumatismo, 2008; 60: Supplemento 1: 50-58
ORIGINAL ARTICLE
Fibromyalgia syndrome:
the pharmacological treatment options
Il trattamento farmacologico della sindrome fibromialgica
P. Sarzi-Puttini1, R. Torta2, F. Marinangeli3, G. Biasi4, M. Spath5, D. Buskila6, R.H. Gracely7,
M.A. Giamberardino8, L. Bazzichi9, M. Cazzola10, M. Di Franco11, S. Stisi12, F. Salaffi13, R. Casale14,
G. Leardini15, R. Gorla16, A. Marsico17, R. Carignola18, L. Altomonte19, F. Ceccherelli20, G. Cassisi21,
G. Arioli22, A. Alciati23, F. Atzeni1 (Italian Fibromyalgia Network)
1Rheumatology Unit, L. Sacco University Hospital, Milan, Italy; 2Department of Neuroscience, University of Turin, A.S.O. San Giovanni Battista of Turin, Turin, Italy; 3Department of Anesthesiology and Pain Medicine, L'Aquila University, L’Aquila, Italy; 4Unit of Rheumatology, University of Siena, Siena, Italy; 5Friedrich-Baur-Institute, University of Munich, Munich, Germany; 6Department of Medicine H, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel; 7Department of Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA; 8Ce.S.I. “G. D’Annunzio” Foundation, Department of Medicine and Science of Aging, “G. D’Annunzio”, University of Chieti , Italy; 9Department of Internal Medicine, Division of Rheumatology, S. Chiara Hospital, University of Pisa, Italy; 10Unit of Rehabilitative Medicine “Hospital of Circolo”, Saronno (VA), Italy; 11Chair of Rheumatology, University la Sapienza Rome, Rome, Italy; 12Rheumatology Unit, “G.Rummo” Hospital, Benevento, Italy; 13Department of Rheumatology, Polytechnic University of the Marche Region, Ancona, Italy; 14Department of Clinical Neurophysiology and Pain Rehabilitation Unit, Foundation Salvatore Maugeri, IRCCS, Scientific Institute of Montescano, Montescano (PV), Italy; 15Rheumatology Unit, SS Giovanni e Paolo Hospital , Venice, Italy; 16Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Italy; 17Rheumatology Unit, Hospital of Taranto, Taranto, Italy; 18Department of Neuroscience, University of Turin, A.S.O. San Giovanni Battista of Turin, Turin, Italy; 19UOC of Rheumatology Hospital S. Eugenio, Rome, Italy; 20IOV (Veneto Cancer Institute), IRCCS, Department of Pharmacology and Anesthesiology, University of Padua, Italy; 21Rheumatology Branch, Specialist Outpatients’ Department, Belluno, Italy; 22Division of Rehabilitative Medicine and Rheumatology, General Hospital of Pieve di Coriano (Mantua), Italy; 23Department of Psychiatry, L. Sacco University Hospital, Milan, Italy RIASSUNTO
Il trattamento farmacologico della sindrome fibromialgica (FM) si è gradualmente arricchito di nuove molecole; tut-tavia, nessun farmaco da solo è in grado di controllare completamente la costellazione dei sintomi che caratterizza-no tale sindrome. Attualmente non è possibile trarre conclusioni definitive sul migliore approccio farmacologico pertrattare la FM, poiché i risultati degli studi clinici controllati presentano limitazioni metodologiche e vi è una consi-stente eterogeneità nelle strategie terapeutiche, che rendono gli studi di difficile confronto. Una varietà di trattamen-ti farmacologici, che comprendono antidepressivi, farmaci antiinfiammatori non steroidei (FANS), oppioidi, sedativi,rilassanti muscolari e anti-epilettici vengono utilizzati per trattare la FM con risultati contrastanti. In questa review,si parlerà principalmente dei farmaci che hanno mostrato i risultati clinici più significativi. La natura della FM sug-gerisce che un approccio terapeutico a più livelli, sia farmacologico che non farmacologico, sembra costituire at-tualmente la decisione terapeutica più appropriata. Reumatismo, 2008; 60: Supplemento 1: 50-58 INTRODUCTION
population is 1-3%, and it is more common amongfemales than males. The American College of Fibromyalgia (FM), also known as fibromyalgia Rheumatology (ACR) classification criteria defines syndrome (FMS), is a frequently observed sys- it as widespread pain with patients endorsing at least temic disorder characterized by widespread muscu- 11 of 18 tender points as painful (3). Although its loskeletal pain (1, 2). Its prevalence in the general defining feature is chronic, widespread pain, FM pa-tients may also have a number of other symptoms including sleep disturbance, fatigue, irritable bowel syndrome, headache and mood disorders (1). Director of Rheumatology UnitL. Sacco University Hospital, Milan, Italy Current evidence advocates a multifaceted program emphasizing patient education, medications for im- Fibromyalgia syndrome: the pharmacological treatment options 51
proving symptoms, and aggressive use of exercise NSAIDs among patients; but the authors stress that and cognitive-behavioural approaches to retain or if safety and costs are issues, then the recommen- restore function (4-6). Physicians and patients dation of the American College of Rheumatology should be educated about current theories regard- that acetaminophen be the first choice, primarily ing the underlying pathophysiologic mechanisms for mild pain, seems appropriate given the long du- of FM, and then set realistic goals for all modali- The use of NSAIDs or acetaminophen, with or However, it is not possible to draw definite con- without opioids, is always justified when patients clusions concerning the best approach to managing who already suffer from FM have other peripheral FM because results of randomized clinical trials sources of pain (osteoarthritis, inflammatory arthri- present methodological limitations, and therapeu- tis, degenerative disk disease) (11).
tic programs are consistently heterogeneous, which Opioids are meant to improve function in FM pa- renders them difficult to compare (7,8). However, tients who are impaired by pain, even though there a variety of pharmacological treatments, including is an open debate about their usefulness and safe- analgesics, antidepressants, antiepileptics and ty as a “specific” medication for fibromyalgia pa- many other drugs have been used to treat symptoms of FM with mixed results (8). In this review, we Few clinical trials exist that address the use of opi- will discuss those drugs that have produced the oids to treat persistent pain in FM patients, but most significant clinical results in treating FM pa- those trials show that these drugs are helpful for re- lieving FM pain; moreover, opioids can help to re-duce sleep disturbances, anxiety and depression Analgesics
and to increase mobility and enjoyment of life (13, The use of steroids and nonsteroidal anti-inflam- matory drugs (NSAIDs) in FM has had disap- Potential side effects tend to decline over time, and pointing outcomes (1, 8). NSAIDs, which are com- addiction has been disproven by the scientific lit- monly used for arthritic conditions, may be less ef- fective for FM because pain associated with FM is Opioids that are available on the Italian market in- not caused by muscle or joint inflammation. There clude codeine, tramadol, oxycodone, hydromor- is no scientific evidence that NSAIDs are effective phon, morphine, buprenorphine and fentanyl. when used alone in FM patients, although they may Furlan et al. (15) conducted a meta-analysis of 41 be useful adjuncts for analgesia when combined randomized trials (6019 patients, 7% affected by with tricyclic medications (1); the combination of FM) to evaluate the efficacy of opioids ranging in NSAIDs with benzodiazepines, however, gave in- duration from 1-16 weeks. They found that opi- oids were more effective than placebo for both pain The central nervous system (CNS) mechanisms for and functional outcomes; and strong opioids were the disorder, specifically, central sensitization, cen- significantly superior to naproxen and nortripty- tral disinhibition and a dysfunctional hypothalam- line, but only for pain relief. Despite the relative ic-pituitary-adrenal axis, could justify the relative- brevity of the trials, more than 1/3 of the partici- ly reduced efficacy of NSAIDs and opioids, the latter being more effective for “peripheral” pain Tramadol, in particular, was beneficial for FM pa- (7). However, NSAIDs can be helpful in reducing tients (8, 9, 12-14). It is an atypical pain reliever pain that flares with excessive physical activity, that differs from other narcotics in its action on the tendinitis or bursitis; but they should be used only central nervous system, specifically, on reuptake as needed to avoid side effects. COX inhibitors of serotonin and norepinephrine. Its most common have much fewer side effects, but have less effica- side effects are drowsiness, dizziness, constipation and nausea, and it should not be given in combi- Acetaminophen acts differently for FM patients; it has a degree of strength for FM and is safe for use Tramadol, used alone or in combination with ac- over long periods (9). Wolfe et al. surveyed etaminophen, is commonly prescribed for relief of rheumatic disease patients about their preferences fibromyalgia pain (16-18) in a dose of 200-300 for NSAIDs versus acetaminophen in terms of ef- mg/d. A small double-blind, placebo-controlled tri- ficacy and side effects (10). There was a consider- al initially suggested that tramadol was effective able and statistically significant preference for and well-tolerated in patients with FM (16). 52
A larger RCT (n=69) reported decreased visual not necessary for legal purposes, it would help to analogue pain scores, improved pain relief and de- educate patients and give them a sense of respon- creased pain threshold after tramadol treatment.
Another study compared a combination of 37.5 mg It is appropriate to increase doses of immediate-re- tramadol/325 mg acetaminophen tablets with lease opioids slowly until pain reduction is placebo in 315 patients with FM. Pain and physi- achieved and then switch patients to controlled-re- cal functioning improved significantly in the tra- lease opioids, considering that most patients with madol/acetaminophen-treated subjects. The aver- chronic, non-malignant pain can be managed with age dose of tramadol/acetaminophen was 4.0±1.8 <200-300 mg/d of morphine (or equivalent).
tablets per day with an attrition rate of 19% (n=29) When opioids prove to be necessary, they must, of due to adverse events. The attrition rate in the course, be used with extreme caution. Patients placebo-treated subjects was 12% (n=18). This should be evaluated periodically for continuing study suggested that the combination of tra- pain relief, side effects and indications of depen- madol/acetaminophen was effective in treating FM dence. They must be closely monitored, must agree patients’ pain without causing serious adverse to seek psychotherapy and must complete a signed agreement to communicate with a single prescrib- Bennett et al. (18) examined efficacy data to com- ing physician and a single dispensing pharmacy. pare the impact of tramadol/acetaminophen versus As with any chronic pain syndromes, patients placebo on quality of life; the authors concluded that should be carefully selected for opioid therapy, and moderate-to-severe fibromyalgia pain significantly a plan for appropriate follow-up and monitoring impairs health-related quality of life (HRQOL) in for pain reduction, outcome improvement, side ef- fects and misuse should be clearly outlined. The in- A recent study has demonstrated that transdermal terdiction of all opioid medications is inappropri- buprenorphine, a strong opioid, has beneficial ef- ate because some patients cannot achieve a rea- fects on severe widespread pain (VAS >6/10), but sonable quality of life and daily functioning with it is less effective on other symptoms that are typ- Harris, et al. (20) have tried to investigate the ap- FM that is diagnosed according to the ACR crite- parent insensitivity of FM patients to opioids. Us- ria seems to include patients with different pain ing positron emission tomography (PET), they processing mechanisms. Screening for disorders found that FM patients, compared to healthy, that may initiate or exacerbate symptoms of FM is matched controls, had reduced µ-opioid-receptor critical; if comorbid disorders are not identified (MOR)-binding potential (BP) in the nucleus ac- early and treated appropriately, therapies that tar- cumbens, the anterior cingulate and the amygdala.
These areas of the brain are known to play a role In fact, there is a subset of FM patients that do not respond to opioids, while other patients, who may These findings indicate altered endogenous opioid have overlapping conditions such as diabetes, analgesic activity in FM and suggest a possible ex- chronic myofascial pain, temporomandibular joint planation for the reduced efficacy of exogenous disorder, arthritis, degenerative disc disease and other diseases, may benefit quite significantly fromopioids (8, 18).
Antidepressants
Physicians should obtain a careful medical and psy- The treatment of pain requires a multimodal ap- chological profile of the patient before prescribing proach that has to consider not only somatic aspects opioids (17, 18). Therapy with these drugs should (i.e., pain onset, location, quality, quantity, dura- be initiated after an adequate trial of aceta- tion, aggravating and alleviating factors), but also minophen for nociceptive pain and of tricyclic an- emotional aspects (i.e., mood and anxiety), cogni- tive aspects (i.e., coping styles, beliefs about pain), To obtain a synergistic effect on analgesia, some and environmental aspects (i.e., social context and patients may be prescribed combinations of differ- patients’ relationships) (1, 2, 8). The hypothesis ent pain relievers (multimodal analgesia) with dif- that pain, anxiety, chronic stress and depression ferent effects on pain pathways, but not for man- share common pathogenetic backgrounds which aging side effects. Patients should be asked to give are represented by neurotransmitters and immune informed consent for treatment; even though it is response is noteworthy. As such, depression must Fibromyalgia syndrome: the pharmacological treatment options 53
be considered as a systemic disease that is related depressants (TCA) or SNRIs (serotonergic and no- not only to neurotransmission imbalance, but also radrenergic reuptake inhibitors), seems more ef- to other neurotrophic, neurosteroidal, CNS hor- fective in treating pain, and FM, in general, than in- monal modifications and diffuse, autonomic, im- hibition of either transporter alone using selective munologic, and metabolic somatic changes (8, 21).
serotonergic (SSRIs) or noradrenergic (NARIs) re- According to this hypothesis, antidepressants re- store neurotransmitter levels and modulate recep- However, the efficacy of TCAs is counterbalanced tor expression in the hypothalamus, which nor- by side effects (32, 33), while the better-tolerated malizes hyperactivity of the hypothalamic-pitu- SSRIs demonstrate less effectiveness in treating fi- itary-adrenal (HPA) axis (18, 1). An over-activation of the HPA axis is observed in depression and in Antidepressants acting both on NE and 5HT in- chronic stress, both of which are frequently present duce a contextual increase of the endogenous opi- in patients with long-term pain disorders. Con- oid system response that raises the pain threshold versely, the response to stress is considered to play at the periacqueductal level and increases the gate a crucial role in the pathogenesis of several syn- control of nociception at the spinal cord level (38).
dromes, such as FM, chronic fatigue syndrome and Antidepressants usually produce a fast, direct anal- irritable bowel syndrome (22, 23). Similarly, auto- gesic effect (on opioid, enkephalinergic, substance nomic system alterations, such as sympathetic P) that is independent of mood state; it first ap- overactivity, are present in both depression and FM pears after a few hours and can be achieved with (21). Finally, pro-inflammatory cytokines within the CNS play a role in the pathophysiology of After a longer period of 2-3 weeks, a more robust mood disorders (and pain), and modulating these analgesic effect develops when antidepressants cytokines via chronic antidepressant treatment con- have a more profound influence on mood and anx- tribute to improve depression (and pain) (24). iety, and the affective and cognitive components of Several studies reported high frequency of mood pain become regulated. This effect can only be pro- disorders in FM patients (25, 26) compared to con- duced with full doses that are easier to achieve with trols (27). Short-term clinical studies have shown the new generation of antidepressants, such as SS- efficacy for antidepressants in the treatment of FM Concerning the use of antidepressants in fi- Abnormalities in central monoaminergic neuro- bromyalgia, Perrot and colleagues (41) identified transmission that are observed in depression might forty-nine publications on the use of antidepres- play a role in FM pathophysiology because dys- sants to treat painful rheumatologic conditions (in- function of 5-HT– and NE-mediated descending cluding 37 studies and 12 meta-analyses) that were pain-inhibitory pathways is an important mecha- considered valid and used to develop the following nism related to the pain experienced by FM pa- considerations: the analgesic effect is higher for tients. Antidepressants that increase 5-HT and NE- TCAs than SSRIs; clear evidence concerning dose- mediated neurotransmission are commonly used to response does not exist; the onset of action occurs treat FM and other chronic pain conditions, partic- within a week; the route of administration is oral; ularly neuropathic pain. Inhibition of both the 5-HT and side effects are more prevalent in TCAs than and NE reuptake transporters using tricyclic anti- SSRIs. Unfortunately, this review included studies Table I - Summary of the controlled studies of dual reuptake inhibitors (SNRI).
VLF = venlafaxine; DUL = duloxetine; MIL = milnacipran; dose in mg/day; outc. = outcome measures: VAS = Visual Analog Scale; FIQ = Fibromyalgia Impact Questionnaire; 54
from 1966 to 2003 and did not consider new anti- Anticonvulsants/antiepileptic drugs
depressants such as SNRIs that are less effective Antiepileptic drugs (i.e., gabapentin and prega- than TCAs but remarkably more tolerated, partic- balin) act at a number of sites that may be relevant to pain. The precise mechanism of their analgesic Antidepressants that act on both NE and 5HT, i.e., effect remains unclear, but it is thought that they SNRIs (Serotonergic and Noradrenergic Reuptake limit neuronal excitation and enhance inhibition Inhibitors), are venlafaxine, duloxetine and mil- (53). The relevant sites of action include voltage- nacipran (milnacipran is not marketed in Italy).
gated ion channels (i.e., sodium and calcium chan- Only a few controlled studies are available to date; nels), ligand-gated ion channels, excitatory recep- these are summarized in Table I (43-46). All of tors for glutamate and Nmethyl-D-aspartate, the these controlled studies demonstrated a significant inhibitory receptors for gamma-aminobutyric acid superiority of the SNRI over placebo, and report- ed few and mild side effects (more frequent nau- In preclinical pain models, gabapentin is a struc- sea, dry mouth and constipation in the first two tural analogue of the neurotransmitter GABA; it ex- erts robust analgesic and anti-allodynic effects in Cyclobenzaprine, a tricyclic muscle relaxant, has syndromes that are secondary to sensitization of also proven to be moderately effective in FM pa- pain responses but has minimal effects in models tients at a dose of 10-40 mg/day (48). This has re- of acute, transient pain (55). Taylor, et al. (56) sug- cently been confirmed by a meta-analysis of five gested that gabapentin did not appear to reduce randomised, placebo-controlled trials (49), which acute pain from injury, but appeared to be effective showed that patients treated with cyclobenzaprine in reducing abnormal hypersensitivity (allodynia were approximately three times as likely to report and hyperalgesia) induced by inflammatory re- symptom improvement, but there was a high sponses or nerve injury. The antinociceptive effects dropout rate and the duration of the studies was of gabapentin are hypothesized to be mediated by modulation of calcium channels via binding, mod- In our experience treating cancer pain with antide- ulation of transmission of GABA, and possibly oth- pressants, we have found that the impact of anti- er additional unidentified mechanisms.
depressants on emotion and cognition is quite in- Arnold, et al. (57) conducted a 12-week, random- teresting: after a month of treatment, especially ized, double-blind study that was designed to com- when brief psychotherapy is also included, patients pare gabapentin (1,200-2,400 mg/day; n=75 pa- who have pain as well as maladaptive coping styles tients) versus placebo (n=75 patients) for efficacy (such as despair or hopelessness) begin to adopt and safety in treating pain associated with FM. Pa- positive coping styles (such as fighting spirit). This tients who were treated with gabapentin displayed change is obtained by improving mood and re- significantly greater improvements in the Brief shaping beliefs about pain, both of which are ex- Pain Inventory (BPI) average pain interference tremely important in malignant pain diseases (50).
score, the Fibromyalgia Impact Questionnaire A final consideration involves the placebo effect in (FIQ) total score, the Clinical Global Impression of Severity, the Patient Global Impression of Im- In a medical model placebo is manly considered an provement, the Medical Outcomes Study (MOS) inert substance, and at present, it is well known Sleep Problems Index, and the MOS Short Form 36 that the placebo effect on pain is mediated by an vitality score; but they did not show improvements in the mean tender point pain threshold or the In clinical practice, however, we consider that a Montgomery Asberg Depression Rating Scale.
placebo effect is also an adjunct response to an ac- Gabapentin was generally well tolerated by these tive drug: the individual expectation of a positive response will increase the pharmacological action Pregabalin is an α -δ ligand that has analgesic, anx- of the drug, while a negative expectation will re- iolytic-like, and anticonvulsant activity in animal duce the effectiveness of the therapy (nocebo ef- models. Biochemical studies identified α -δ (type 1) as the primary binding site for both pregabalin The placebo effect is highly related to the rela- and the related compound, gabapentin (57). Al- tionship between patient and physician (52), a re- pha -delta is an auxiliary protein associated with lationship that is also important in affecting phar- voltage-gated calcium channels. Potent binding of pregabalin at the α -δ site reduces calcium influx Fibromyalgia syndrome: the pharmacological treatment options 55
at nerve terminals (58) and, therefore, reduces the Other drugs
release of several neurochemicals, including glu- Serotonergic receptors have been implicated in pro- tamate, noradrenaline, and substance P (58, 59).
cessing information and in the development of pain The reduced neurotransmitter release caused by in FM, and randomised, controlled trials have drug binding at the α -δ site is presumed to ac- found that tropisetron, a 5-hydroxytryptophan in- count for the the analgesic, anticonvulsant, and termediate metabolite of L-tryptophan, is more ef- anxiolytic-like actions of pregabalin in animal models. Reduction of neurotransmitter release from In a pilot study, Papadopoulos, et al. (66) found that neurons in the spinal cord and brain is also pro- tropisetron might be effective in treating pain in FM posed as the mechanism of action that may result patients, but Koeppe, et al. (67) did not observe in clinical benefit for patients with FM. In an 8- any significant change in the intensity of habitual week, multicentre, double-blind, randomised, pain following local injection of tropisetron in FM placebo-controlled clinical trial, Crofford, et al.
patients who took part in a pre- and post-treatment, (61) compared the effects of pregabalin (150, 300 double-blind study of pain perception and central and 450 mg/day) on pain, sleep, fatigue and health- related quality of life in 529 FM patients, and found In an open trial of pindolol, a mixed serotonin (5- that it was superior to placebo in reducing the HT)(1A) presynaptic autoreceptor/beta-adrenergic scores for pain, SF-MPQ, sleep index, fatigue, pa- receptor antagonist, at a dose of 7.5 mg/day (titrat- tient and clinician global impression of change, ed to a maximum of 15 mg/day) for a total of 90 and four of the eight SF-36 domains. The most fre- days in 20 female FM patients, Wood, et al. (68) quent adverse events were dizziness and somno- demonstrated a significant improvement in prima- ry tender point counts (p<0.001), tender point Arnold, et al. (62) conducted a study to assess scores (p<0.001), and FIQ (p<0.005). The depres- symptoms of anxiety and depression in a large co- sion and anxiety scores did not significantly change hort of FM patients to determine the impact of among the women who completed the study, and these symptoms on pain during a course of prega- the impact on cardiovascular parameters was clin- balin treatment. The results indicated that anxiety symptoms were more common than depressive Despite the suggestion of relative growth hormone symptoms in this cohort, and that the pain treatment (GH) deficiency in FM patients and reports of im- effect of pregabalin did not depend on baseline provements after the administration of GH injec- anxiety or depressive symptoms, which suggests tions, the enthusiasm for this approach has been that pregabalin improves pain in patients with or dampened by the appearance of adverse effects, without these symptoms. Finally, much of the pain the need for frequent injections, and its high cost reduction appears to be independent of improve- Low doses of a β-blocker have been tried in se- In a multicenter, double-blind, placebo-controlled lected cases with prominent autonomic symptoms, trial, Mease, et al. (63) randomly assigned 748 FM such as palpitations and orthostatic tachycardia; patients to receive placebo or pregabalin (300, 450, however, the effects are not known (68).
or 600 mg/day, dosed twice daily) for 13 weeks.
Lidocaine hydrochloride injections, botulinum tox- The pregabalin groups showed statistically signifi- in injections, are sometimes offered to patients with cant improvements in mean pain score and in Pa- tient Global Impression of Change (PGIC) com-pared to the placebo group. Improvements in FIQ-Total Score for the pregabalin groups were numer- CONCLUSIONS
ically but not significantly greater than those for theplacebo group. Compared with placebo, all prega- The success of the current treatments for FM is balin treatment groups showed statistically signifi- still limited, and there is a need for the develop- cant improvement in assessments of sleep and in ment of new drugs that are targeted at the CNS, and patients’ impressions of their global improvement.
that undergo efficacy and toxicity testing in long- Dizziness and somnolence were the most fre- term, comparative trials involving large numbers of quently reported adverse events. The study con- patients. Recent data concerning polymorphisms cluded that pregabalin monotherapy provides clin- of the genes in the serotonergic and dopaminergic ically meaningful benefit to patients with FM.
systems may facilitate the development of a more 56
rational, genotype-based, pharmacological ap- candidates for dopaminergic medications (73). proach (72). Subjects with the short 5HTTLPR al- Certainly, further randomized, controlled clinical lele in the serotonergic system may be more suit- trials that are conducted with subgroups of patients able candidates for antidepressant treatment (73), using standardized outcome measurements and suf- whereas subjects with polymorphisms in the ficient length of follow-up are necessary to observe dopaminergic system, such as the dopamine D4 and document changes in patient symptoms and receptor exon III repeat polymorphism, may be Pharmacological treatment has been gradually enriched by a variety of compounds; however, no single drug is capa-ble of fully managing the constellation of fibromyalgia (FM) symptoms. Currently, it is not possible to draw definiteconclusions concerning the best pharmacological approach to managing FM because results of randomized clinical tri-als present methodological limitations and therapeutic programs are too heterogeneous for adequate comparison. How-ever, a variety of pharmacological treatments including antidepressants, nonsteroidal anti-inflammatory drugs(NSAIDS), opioids, sedatives, muscle relaxants and antiepileptics have been used to treat FM with varying results. Inthis review, we will evaluate those pharmacological therapies that have produced the most significant clinical resultsin treating FM patients.
The nature of FM suggests that an individualized, multimodal approach that includes both pharmacologic and non-pharmacologic therapies seems to be the most appropriate treatment strategy to date.
Key words - Pharmacologic approach, non-pharmacologic approach, opioids, antiepileptics, nonsteroidal anti-in-
flammatory drugs.
Parole chiave - Terapia farmacologica, terapia non-farmacologica, oppiodi, antiepilettici, anti-infiammatori non
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