Treatment of fibromyalgia: a changing of the guard Andrew J Holman
Fibromyalgia remains one of the most common and enigmatic musculoskeletal disorders Pacific Rheumatology among patients with pain and, until recently, few effective treatments have been Associates Inc., PS 4300, Talbot Road South, discovered. This review will briefly consider the rationale supporting traditional treatment Suite 101, Renton, options and their efficacy, including the role of exercise and pharmacotherapy. Juxtaposed Washington, USA with these common approaches to relieve fibromyalgia pain and fatigue are the promising Tel.: +1 425 235 9500;Fax: +1 425 235 9555; new medications that are being developed, such as pregabalin, milnacipran, duloxetine, sodium oxybate, ropinirole and pramipexole. Outcomes from recent randomized trials will be reviewed and compared.
Few medical disorders generate as much contro- induction of FMS symptoms with specific dis- versy as fibromyalgia syndrome (FMS). Its enig- ruption of deep, non-rapid eye movement matic pathogenesis and plethora of ineffective (nREM), stage IV sleep [7], have encouraged treatment strategies confound physicians and consideration of how sleep affects a variety of frustrate afflicted patients and their families.
CNS functions influencing pain, fatigue and Despite the introduction of the term fibrositis in cognitive behavior. Sophisticated measure- 1904 by Gower [1], progress in understanding ments of autonomic regulation with validated FMS has been slow. However, recent innovative tools, including heart rate variability and tilt- strategies and broader investigation of its cause table testing, have increased the awareness that beyond a myopic focus on psychiatric or patients with FMS fail to maintain normal musculoskeletal research have finally led to a new sympathetic homeostasis [8–14]. In turn, per- expectation of improved treatment outcome.
turbed sleep, psychiatric arousal (e.g., post- Firm confidence in a diagnosis is essential traumatic stress disorder, bipolar disorder and before formulating and implementing an effec- anxiety disorder), peripheral vasomotor tone, tive treatment strategy in any medical condition.
cardiac rhythm and bowel motility focus future For many clinicians, the diagnosis of FMS research directly on new autonomic mecha- remains confusing despite validated criteria pub- nisms that may lead to an improved under- lished by the American College of Rheumatol- standing of FMS.
ogy in 1990 (Box 1) [2]. While specific tenderness,
Almost 85% of FMS cases occur in women, but or tender points, have been promoted as diag- men are often undiagnosed. In fact, the divergent nostic evidence of this disorder, honest debate presentation of FMS in men compared with and, at times, unruly skepticism, is evident even women has been well reported [15]. Pain and mus- among rheumatologists. While helpful as inclu- cular spasm are generally more diffuse and vague sion criteria for research studies, fibromyalgia in men. It appears that the hallmark diagnostic tender-point intensity can still vary from day to finding in FMS, 11 of 18 specific tender points, day in clinical practice, leading to diagnostic becomes apparent to the clinician and male uncertainty. Nevertheless, clinicians can readily patients much later in its clinical course. Response recognize and attempt to treat the common pres- rates (RRs) to a variety of pharmacologic options entation of chronic, unexplained, widespread are also less robust in men. The cause of these gen- pain, tenderness and fatigue of fibromyalgia.
der differences in presentation and response is There is no consensus regarding pathogene- uncertain, but may relate to behavioral differences, Keywords: dopamine agonist,
duloxetine, fibromyalgia,
sis, but an abnormality of centrally mediated comorbidities or hormonal variations, including milnacipran, pramipexole, pain processing has gained greater acceptance clinically amenable testosterone deficiency in men pregabalin, ropinirole, receiving chronic opioids.
[3]. Functional magnetic resonance imaging(fMRI) [4] and pain-testing studies [5] have sig- The variability and unpredictability of treat- nificantly strengthened this concept of cen- ment response has fueled clinician skepticism trally amplified pain perception. Observations regarding FMS as a specific disorder, and gender of abnormal sleep-stage architecture [6] and differences also enhance this debate. Some 10.2217/17455057.1.3.409 2005 Future Medicine Ltd ISSN 1745-5057 Women's Health (2005) 1(3), 409-420
REVIEW – Holman Box 1. The 1990 American College of Rheumatology criteria for the classification of

• History of widespread pain. Definition: - Pain is considered widespread when all of the following are present: - Pain in the left side of the body - Pain in the right side of the body - Pain above the waist - Pain below the waist - In addition, axial skeletal pain (cervical spine or anterior chest or thoracic spine or low back) must be present. In this definition, shoulder and buttock pain is considered as pain for each involved side. Low back pain is considered lower segment pain• Pain in 11 of 18 tender point sites on digital palpation. Definition: - Pain, on digital palpation, must be present in at least 11 of the following 18 tender point sites: - Occiput: bilateral, at the suboccipital muscle insertion - Low cervical: bilateral, at the anterior aspects of the intertransverse spaces at C5–C7 - Trapezius: bilateral, at the midpoint of the upper border - Supraspinatus: bilateral, at origins, above the scapula spine near the medial border - Second rib: bilateral, at the second costochondral junctions, just lateral to the junctions on - Lateral epicondyle: bilateral, 2 cm distal to the epicondyles - Gluteal: bilateral, in the upper outer quadrants of buttocks in anterior fold of muscle - Greater trochanteric: bilateral, posterior to the trochanteric prominence - Knee: bilateral, at the medial fat pad proximal to the joint - Digital palpation should be performed with an approximate force of 4 kg. For tender point to be considered positive the subject must state that the palpation was painful. Tender is not to be considered painful *For classification purposes, patients will be said to have fibromyalgia if both criteria are satisfied. Widespread pain must have been present for at least 3 months. The presence of a second clinical disorder does not exclude the diagnosis of fibromyalgia.
Adapted from [2].
explain this paradox by considering FMS as a Traditional treatment family of disorders and suggest defining FMS Treatment of FMS has been effectively reviewed subsets to improve treatment outcomes for spe- over the past few years, but these authors tend to cific medications [16]. Unfortunately, the impor- favor more traditional approaches [17]. Until the tance of comorbidities accompanying FMS and ‘magic bullet' is discovered, a balanced and compre- interfering with the treatment response has been hensive approach appears reasonable. Many differ- given little consideration. Due to the general ent clinical specialties, including clinicians, vagueness of fatigue and widespread pain as chiropractors, naturopaths, massage therapists, symptoms, most clinicians find teasing apart physiotherapists, acupuncturists and psychologists, comorbidities particularly difficult in patients are inundated with patients searching for assistance.
with FMS. Nevertheless, defining all accompa- Often these modalities have provided a benefit.
nying causes of pain when treating FMS, such as Even among nonbelievers, most clinicians arthritis, myelopathy, bursitis, tendonitis and encourage exercise for patients with FMS. In migraine to name a few, is as important as iden- 1988, a randomized trial of exercise demonstrated tifying all risk factors for cardiovascular disease.
improvement in FMS pain threshold compared Pain and tenderness should be widespread in all with flexibility training after 20 weeks [18]. Aerobic four limbs and the axial spine. FMS is not a diag- exercise [19], muscle strengthening, pool exercises nosis of exclusion. One must be confident of the [20] and spa therapy [21] have been found to be diagnosis and even more aware of comorbidities helpful. Many studies supportive of exercise vary before considering treatment or evaluating a treat- in methodology and have significant limitations, ment response. Effective treatment of other causes including inadequate blinding and small sample of pain, stress, insomnia and autonomic dysfunc- size. However, a thorough review by Goldenberg tion are equally important to the overall outcome and colleagues concluded that all patients with as the choice of treatment for FMS.
FMS should begin a cardiovascular program [22].
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Treatment of fibromyalgia – REVIEW Analysis of these exercise studies reveals with amitriptyline (25 mg at bedtime) [31]. In important limitations, including appropriate this four-arm, 6-week, double-blind, crossover matching of specific therapies with hetero- study, fluoxetine alone and amitriptyline alone geneous patients and consistent adherence to improved pain and global function, but not exercise regimens [23]. In addition, while statis- fatigue or tender-point score. Combined, in the tical significance was routinely achieved, the fourth arm, improvement in pain and fibro- magnitude of the benefit (25–30% improve- myalgia impact questionnaire (FIQ) score ment) would not be considered robust. Most improved maximally (34%). Other studies with clinicians note that many of their patients with amitriptyline alone have confirmed a statisti- FMS fail to respond to exercise and many cally significant decrease in FMS pain of decline, or are unable to participate in such approximately 30% [32]. Uncontrolled reports structured programs implemented at an experi- of serotonin (5-hydroxytryptamine [5-HT]) enced research facility. Regrettably, outcomes reuptake inhibitors, including sertraline [33], from many exercise trials simply do not trans- also suggest modest efficacy.
late into clinical practice. The second most frequently studied drug for The notion of exercise as an effective thera- the treatment of FMS is cyclobenzaprine.
peutic options for FMS may have arisen from Dosed at 10–30 mg at bedtime, a meta-analy- the observation that aerobic fitness may be pre- sis of randomized studies demonstrated a bene- ventative. In 1975, Moldofsky induced wide- fit similar to amitriptyline [34]. Even doses as spread pain suggestive of FMS by disrupting low as 1–4 mg at bedtime have demonstrated stage IV sleep with an auditory arousal for some analgesic efficacy and improved sleep- 4 nights in healthy college students [6]. Similar stage architecture [35]. Decreased levels of cere- results did not occur when he repeated the exper- brospinal fluid (CSF) neuroamines and sub- iment in fit military recruits or after disruption stance P were reported by Russell with of REM sleep stages [7]. It is not clear how fitness tizanidine 4–24 mg each day [36]. Carisoprodol preserves the benefits of stage IV sleep, but dosed at 1200 mg/day decreased FMS pain incorporation of aerobic exercise into an FMS compared with placebo in one study [37], but treatment strategy remains popular.
this result has not been confirmed. Other mus- Evidence that other nonpharmacologic rem- cle relaxants are routinely used by clinicians edies are effective is debatable, yet accepted by without literature support.
many clinicians. Soft-tissue injection with Other classes of medication available to treat saline, local anesthetics and/or corticosteroids FMS have not demonstrated efficacy compared have been offered to patients with FMS, but with placebo, including ibuprofen placebo-controlled trials are unavailable. Acu- (2400 mg/day for 3 weeks) [38], naproxen puncture may reduce pain and analgesic (1000 mg/day for 6 weeks) [39] or prednisone requirements, but of three controlled studies (15 mg/day for 2 weeks) [40]. Temazepam [24–26], only one demonstrated a significant (15–30 mg at bedtime for 12 weeks) demon- treatment benefit compared with placebo. Mas- strated a modest statistical benefit [41], but alpra- sage [27], ultrasound [28] and mineral baths [29] zolam (0.5–3.0 mg at bedtime) was not superior demonstrate a benefit for pain compared with to placebo [42]. Finally, a randomized 13-week placebo, but sustained meaningful improve- trial of tramadol in combination with acetami- ment is unusual. Cognitive behavioral therapy nophen in 315 subjects demonstrated signifi- has become a logical and helpful therapeutic cant analgesic efficacy without any serious approach for FMS [30], but many patients lack adverse effects [43].
access to skilled therapists.
A controlled trial of zolpidem (Ambien®, In 2004, Goldenberg and colleagues pro- Sanofi-Synthelabo) may provide an important vided an evidence-based review of FMS illustrative example. As a sedative hypnotic, management [22]. Their assessment of FMS zolpidem induces stage II rather than stage IV studies based on study size, design and repro- sleep. Subjects noted improved sleep duration ducibility is clearly the most thorough review of and decreased sleep latency, but did not note traditional treatment options for FMS to date.
improved FMS pain or fatigue compared with The greatest improvement in pain as an out- subjects receiving placebo [44]. Perhaps, if the come variable compared with placebo was also medication effectively restored depleted stage IV reported by Goldenberg in 1996, in a study of sleep, an improvement in FMS symptoms may fluoxetine (20 mg each morning) combined have been found.
REVIEW – Holman Finally, although controlled trials are and 77% completed the trial. All active arms unavailable, the safety of clonazepam and improved within approximately 2 weeks and lorazepam in 160 patients over 12 months was demonstrated sustained improvement through to encouraging [45]. Patients did not escalate their week 8. Treatment with pregabalin was associated bedtime dose (2.0 mg) or note significant with statistically significant dose-dependent adverse events, including withdrawal seizures.
improvement. However, improvement in pain Contrary to other benzodiazepines, lorazepam score was modest, even in the 450 mg arm (-0.93, and clonazepam effectively reduce restless legs 1–11 scale), and the p-value (p = 0.0009) syndrome (RLS) symptoms [46], a common reflected the large size of the study. Adverse events source of arousal fragmenting sleep quality in were common, but mild and transient, including patients with FMS.
dose-dependent dizziness (49% in the 450 mgarm vs 11% for placebo). Somnolence (28%), dry New pharmacologic treatment options mouth (13%), peripheral edema (11%) and Research in fibromyalgia has grown exponen- weight gain (7%) were also more common with tially and new, meaningful treatment options are pregabalin than placebo.
now at hand. Every clinician brave enough to Pregabalin represents an extension of the neu- accept patients with FMS recognizes many ropathic/anticonvulsant therapeutic approach obstacles that interfere with successful treatment.
to FMS. While psychiatric medications have However, embracing a team approach, identifi- been the mainstay of FMS pharmacopeia, many cation of important comorbidities and consider- pain centers have addressed pain, and FMS spe- ation of novel medications are improving cifically, as a neuropathic pain [50]. Narcotic outcomes. In addition, large pharmaceutical analgesic efficacy for FMS has been mixed [51], companies are engaged in a race to discover an but anticonvulsant medications have become effective treatment. Pregabalin (Lyrica™, Pfizer), very popular based on anecdotal evidence. In milnacipran (Dalcipran®, Cypress Bioscience), fact, off-label use of gabapentin has been so duloxetine (Cymbalta®, Eli Lilly), sodium oxy- widespread in North America that the US Food bate (Xyrem®, Orphan Medical/Jazz Pharma- and Drug Administration (FDA) fined its origi- ceuticals) and the dopamine agonists, ropinirole nal manufacture, Warner-Lambert (Parke-Davis (Requip®, GlaxoSmithKline) and pramipexole division, NJ, USA), for promoting unapproved (Mirapex®, Boehringer-Ingelheim) head the list uses [101]. To date, there are no FDA-approved of promising new therapies for FMS.
medications indicated for the treatment ofFMS, and evaluation of innovative off-label FMS therapies has become more difficult in the In the largest controlled trial for FMS to date with USA following this reprimand.
528 patients, pregabalin demonstrated significantimprovement in pain score, sleep quality, fatigue and global measures of change [47]. Pregabalin, a The dual 5-HT and NE reuptake inhibitors precursor of gabapentin (Neurontin®, Pfizer), has (SNRIs) have received widespread attention as analgesic, anxiolytic and antiepileptic effects in the next breakthrough for patients with FMS.
animals. It is a ligand for α2-δ subtype 1 and 2 While a controlled study of venlafaxine receptors that adheres to voltage-gated calcium (Effexor®, Wyeth) was inconclusive [52], two channels without affecting γ-aminobutyric acid case reports suggested a significant benefit at (GABA) receptors [48]. Its activity is limited to higher dosage [53,54]. Milnacipran, a popular neurons and it does not affect vascular calcium antidepressant in Japan, is a novel SNRI that channels. Reduction of calcium influx at the neu- favors reuptake inhibition of NE over 5-HT.
ron reduces release of substance P, glutamate and Reduction of pain in a variety of animal models norepinepherine (NE) [49], which is thought to may be related to the roles of NE and 5-HT in mediate its analgesic and anxiolytic actions.
pain-modulating systems via the descending Subjects were assigned (1:1:1:1) to placebo or inhibitory pathways in the brain and spinal one of three pregabalin doses (150, 300 or cord [55]. Tricyclic antidepressants mediate pain 450 mg/day) for 8 weeks. Demographics for each through 5-HT and NE neurotransmission and group were similar, including 90% women, 95% reduce FMS pain. This potential mechanism of Caucasian, with an FMS duration of 8 years and pain amplification supports the consideration mean pain score of 7 (range: 1 [no pain]–11[worst of SNRIs, which may be better tolerated than pain]). Patients discontinued prior medications tricyclics, for the treatment of FMS.
Women's Health (2005) 1(3)
Treatment of fibromyalgia – REVIEW In a 12-week, double-blind, placebo- Compared with placebo, duloxetine reduced controlled Phase II trial, 125 patients with total FIQ significantly (-5.53, 95% confidence FMS were randomized (3:3:2) to receive mil- interval [CI]: -10.43, -0.63 [p = 0.027]), but did nacipran once or twice daily (up to not reduce the FIQ pain subscore (p = 0.13).
200 mg/day) or placebo [56]. RR was defined as Many other secondary measures of pain were the percentage of subjects who achieved a 50% found to be statistically improved, including the or greater pain reduction by visual analog scale brief pain inventory (BPI), PGIC, number of on an electronic diary. For this outcome mile- tender points, FIQ stiffness subscore and several stone, the intention-to-treat (ITT) analysis RR quality of life measures. A subanalysis revealed for twice daily dosing was 37%, 22% for once- that men with FMS failed to respond to dulo- daily and 14% for placebo. Only the twice- xetine, and that comorbid depression did not daily dose response was statistically superior to influence FMS treatment response. Reported placebo (p = 0.04), but both twice- and once- adverse events were typical of SNRI therapy and daily outcomes on a secondary efficacy meas- included insomnia, dry mouth and constipation ure, the patient global impression of change more frequently than placebo. Duloxetine intol- (PGIC), were superior to placebo (p = 0.003).
erance was mild-to-moderate and did not lead to Multiple components of the FIQ and the significant withdrawal from the study.
short-form McGill pain questionnaire The study was repeated with the exclusion of (SF-MPQ) also showed statistically significant men, the primary outcome was changed and superiority over placebo for both the once- and the sample enlarged to favor a statistically sig- twice-daily dosing arms.
nificant treatment response [58]. The FIQ Adverse events were unremarkable. A became a secondary outcome measure and the Phase III trial has been completed, but details BPI became the primary outcome. In this new have not yet been reported. Milnacipran is not 12-week study, 354 women with FMS were yet available in the USA, but this focus on randomized (1:1:1) to receive duloxetine 60 mg SNRIs and the role of 5-HT and NE in pain daily, 60 mg twice daily or placebo. Pain modulation, and for FMS specifically, represents decreased significantly in subjects treated with a hopeful and increasingly popular approach.
duloxetine (daily and twice daily) comparedwith placebo (p < 0.001), as assessed by the BPI. RR was defined as a 30% (rather than Two large controlled trials of duloxetine have 50%) reduction in pain and was achieved by been recently reported in patients with FMS, 55% in the daily arm, 54% in the twice-daily demonstrating interesting results. Duloxetine is a arm and by 33% in the placebo arm. The size of SNRI approved by the FDA in 2005 for the the study ensured that these differences were treatment of major depressive disorder and statistically significant. The authors' conclu- neuropathic pain associated with diabetic sion, that duloxetine is an efficacious and safe peripheral neuropathy. Its inhibition of 5-HT treatment for FMS, is not unreasonable. How- and NE reuptake is relatively balanced without ever, scrutiny of the two study designs, includ- interacting with opioid, muscarinic, histamine- ing exclusion of nonresponders (men) and 1, α1-adrenergic, dopamine, 5-HT1A, 5-HT1B, changing to a more favorable outcome variable5-HT1D, 5-HT2A and 5-HT3C receptors.
emphasizes the importance of careful review of Once again, in animal models, this SNRI study design.
reduced pain behavior and did so with greaterpotency than venlafaxine, amitriptyline or Sodium oxybate A third treatment approach for FMS focuses These two trials illustrate important issues in directly on sleep physiology and is based on the FMS research. The first trial, reported in 2003, importance of α-wave fragmentation of stage IV randomized (1:1) 207 subjects to duloxetine sleep more than on SNRI- or anticonvulsant- 60 mg twice daily for 12 weeks or placebo [57].
mediated modulation of pain neurotransmis- Demographic variables were equally distributed sion. Diminished slow-wave sleep has been iden- in the two arms and included 87% women (85% tified as an important feature in FMS and Caucasian), with 38% having major depression.
different types of α-wave intrusion of stage IV The coprimary outcomes were FIQ total score sleep have been identified [59,60]. Sodium oxybate (0–80) and FIQ pain subscore (0 [no pain]–10 is a commercially available form of γ-hydroxy- [severe pain]).
butyrate (GHB), a naturally occurring CNS REVIEW – Holman metabolite primarily found in the hippocampus In 2003, the first use of ropinirole for the treat- and basal ganglia. It is the only compound ment of FMS was reported in an open-label known to increase growth hormone secretion assessment of 17 patients who noted a 64% and deep, slow-wave stage IV sleep and is FDA- decrease in tender-point pain score over approved for the treatment of cataplexy in 4 months at a mean dose of 6.0 mg at patients with narcolepsy.
bedtime [62]. While the approved maximum dose A double-blind, crossover trial of sodium for RLS is 4.0 mg at bedtime, the typical dose for oxybate in 24 patients was conducted over Parkinson's disease is 1–8 mg orally three times 1 month intervals with a 2-week washout daily. In 2004, in a controlled trial of 30 patients period [61]. A total of 18 subjects completed the with FMS [63], 20 patients were randomized to trial of sodium oxybate (6.0 mg at bedtime) ropinirole and ten were assigned to the placebo compared with placebo and were monitored by arm. Ropinirole was gradually increased over polysomnogram (PSG), tender-point index and 14 weeks to 8 mg at bedtime. Although 45% of subjective measurements of improvement in patients receiving ropinirole achieved a 50% or daily diaries. A variety of pain and fatigue greater reduction in 10 cm visual analog pain scores improved by 29–33% in the active arm score compared with 30% of placebo patients, compared with 6–10% in the placebo arm the results of this small, pilot study were not sta- (p < 0.005). Tender-point score decreased by tistically significant (p = 0.31). All other meas- 8.4 points with sodium oxybate compared with ures of efficacy (tenderness, fatigue and function) an increase of 0.4 points in the placebo arm also showed a trend towards the efficacy of rop- (p = 0.008). PSG measures of inappropriate inirole compared with placebo.
CNS arousal, including α-intrusion, sleep The most common adverse events were typical latency and REM decreased with treatment, intolerances seen with dopaminergic therapy, while stage III and IV slow-wave sleep increased including mild-to-moderate nausea. Interest- compared with placebo (p < 0.005).
ingly, sudden, uncontrolled daytime sleepiness This study provided preliminary yet compel- (sleep attacks) as well as orthostatic hypotension, ling evidence that FMS pain and fatigue improve experienced by patients with Parkinson's disease with increased slow-wave sleep and decreased treated with daily dopamine agonists, were not α-wave intrusion. A larger, multicenter, control- seen in this FMS trial. Another controlled FMSled study has recently been completed and should trial with a new delayed-release ropinirole for- be reported soon. The therapeutic role of restor- mulation dosed at bedtime has been completed ing stage IV deep sleep to address FMS symp- in Europe, but results are not yet available.
toms provides another important approach quite The rationale for using a dopamine agonist different from treating FMS with analgesics, anti- begins with a greater appreciation of the higher convulsants or SNRIs. Based on Moldofsky's incidence of RLS in patients with FMS (31%) landmark sleep deprivation studies [6,7] and these compared with normal controls (3%) [64]. In May sodium oxybate results, a renewed emphasis on 2005, ropinirole became the first and only medi- the restoration of normal sleep-stage architecture cation approved for the treatment of RLS by the has gained more attention as a primary, rather FDA. This RLS arousal inhibits deep sleep and than secondary, therapeutic goal.
ties in with the Moldofsky findings. While sedat-ing medications are commonly offered to pro- mote deep sleep by overwhelming arousal in Most FMS reviews do not mention dopamine FMS, the dopamine agonist was intended to agonists (e.g., ropinirole and pramipexole), as reduce arousal fragmenting normal sleep.
initial reports were anecdotal until late 2004.
Interestingly, dopamine agonists are not sedat- These medications were FDA-approved for the ing and their mechanism of action in FMS is treatment of Parkinson's disease in 1997 and the under investigation. Abnormal sympathetic reasoning behind their use is far afield of tradi- arousal has been documented in FMS, and these tional approaches to FMS. Ropinirole is a patients maintain poor autonomic homeostasis.
dopamine receptor agonist with specificity for Excessive fight-or-flight responses as well as spe- the dopamine (D)2 and 3 subreceptors (D2, D3). cific arousals such as intense chronic pain, frus-It is metabolized in the liver by the cytochrome tration, post-traumatic stress disorder and P450 (CYP)C1A isoenzyme and has negligible anxiety have been well documented in FMS.
affinity for muscarinic, acetylcholine, α1, α2, Any of these arousals can chronically disruptopioid or 5-HT receptors.
deep, restorative sleep.
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Treatment of fibromyalgia – REVIEW D3 receptors are primarily found in the limbic but were not reported in the placebo arm. One system, including the hippocampus, but not in episode of transient amnesia (< 24 h) required the sympathetic arousal centers in the brainstem.
hospitalization for evaluation, but the patient The hippocampus attenuates and balances sym- fully recovered and completed the trial (double- pathetic arousal [65]. Inadequate dopaminergic blinded) 6 weeks later.
control of autonomic drive from the hippocam- This study was very atypical for a FMS study.
pus has been suggested as a fundamental issue in Subjects were allowed to maintain stable doses of FMS pathogenesis [66]. In fact, preliminary mag- other medications and psychiatric and pain netic resonance imaging (MRI) volumetric comorbidities were allowed. A total of 53 of the assessment has demonstrated hippocampal atro- 59 patients who completed the trial maintained phy in patients with FMS compared with nor- stable doses of other medications, including mal controls [67,68]. Consequently, a medication 50% requiring daily narcotic analgesics. For any capable of decreasing RLS and restoring normal addition of a new medication during the study, hippocampal dampening of brainstem auto- the final untainted assessment was used as the nomic arousal would be a logical therapeutic final outcome. In addition, 30% of subjects were disabled, of whom one returned to work duringthe study (active arm).
Most FMS clinical trials only include patients Although pramipexole is indicated only for the without comorbidities who are willing to wash treatment of Parkinson's disease by the FDA, it out all other medications and risk receiving a also effectively reduces RLS [69]. Its profile is placebo for many months. This bias may affect similar to that of ropinirole, except that it is interpretation of results and question the rele- renally metabolized and has mild affinity for vance of study conclusions for the clinician car- central adrenergic α-2 receptors (the target of ing for patients with comorbidities and moretizanidine and clonidine) in addition to D2 and severe FMS. It is unlikely that future pregabalin,D3 receptors.
milnacipran, sodium oxybate or ropinirole FMS Following two positive open-label reports trials will assess a similarly disabled and narcotic [70,71], a controlled trial of pramipexole for FMS dependent FMS cohort, but perhaps a more tra- in 60 subjects (57 women, 3 men) was recently ditional trial with pramipexole as monotherapy presented [72]. Over 14 weeks, subjects were will be completed. Then, results from these dif- randomized (2:1) to a weekly fixed dose escala- ferent trials may be compared more fairly.
tion of pramipexole from 0.25 to 4.5 mg atbedtime or placebo. Significant reductions in visual analog pain, fatigue, total FIQ score and Potential new therapies for FMS from divergent global function at week 14 were found. The approaches are developing at an unprecedented mean pain score decreased by 36% in the active pace. A comparison of different medications is arm compared with 9% for placebo by ITT shown in Table 1. Scientific principles of FMS are
analysis (p = 0.008). A pain reduction of 50% becoming clearer as basic scientists study neu- or greater was seen in 42% of patients receiving ropharmacology and clinicians observe unex- pramipexole compared with 14% receiving pla- pected benefits and confirm them in randomized cebo. All other secondary outcome measures trials. Application of traditional, conservative trended better for the active arm, including ten- treatments remains an option, but greater RRs der-point index, Beck anxiety score and Hamil- have emerged with the use of medications capa- ton depression scale, without achieving ble of manipulating 5-HT, NE and dopamine.
As with any review of randomized trials, only The most common adverse event was nausea, longer and larger studies can confirm or refute occurring in 79% of the active arm and 71% of these early findings. However, a changing of the the placebo arm. Nausea did not lead to discon- guard is clearly occurring in FMS treatment. tinuation of pramipexole and was addressed byconcomitant use of proton pump inhibitors. A Future perspective mean weight gain of 3 lbs was seen in the pla- Competition among pharmaceutical compa- cebo arm, while 40% of patients in the active nies to discover an effective treatment for the arm noted 5–25 lb weight loss at week 14 millions of patients with FMSa is already lead- (p = 0.001). Transient increased anxiety (14%) ing to dramatic changes in how the medical and vomiting (16%) were seen in the active arm community views this cryptic disorder. Larger REVIEW – Holman Table 1. Comparison of new medications proposed for the treatment of fibromyalgia.
Subjects who achieved 50% reduction of pain (%)
Active arm
Placebo arm
(528 pts/450 mg/8 weeks) (125 pts/200 mg/12 weeks) (207 pts/120 mg/12 weeks) (354 pts/120 mg/12 weeks) (18 pts/6 mg/4 weeks) (30 pts/8 mg/14 weeks) (60 pts/4.5 mg/14 weeks) NR: Not reported; pts: Patients. and bolder studies designed to test these hypoth- arousal of untreated obstructive sleep apnea eses related to central pain processing, auto- could have a significantly negative effect on a nomic regulation and sleep stage architecture, fibromyalgia treatment paradigm designed to enhance the scientific legitimacy of fibromyalgia.
restore deep sleep stages.
As clinicians finally accept the existence of Conversely, comorbidities could explain a FMS, a broader array of individuals may become positive treatment response. Cervical myelo- involved in finding a solution rather than pathy, an autonomic arousal documented in ani- expending energy to rationalize it away with mal models, was also excluded in the mythology. Some of the most vociferous oppo- pramipexole trial. Hypothetically, such a signifi- nents of fibromyalgia are our most gifted clini- cant arousal would limit dampening of auto- cians and researchers. Dedicated fibromyalgia nomic fragmentation of normal sleep by a researchers are a small group who need to be dopamine agonist. However, treatment of fibro- expanded. Bickering over its existence only adds myalgia with pregabalin might be enhanced in to the tragedy of fibromyalgia.
the same subset of patients with fibromyalgia For a variety of medications, study of their and comorbid cervical irritation from cord com- impact on sleep stages and central pain process- pression. Stabilization of neural membrane activ- ing is also expanding our knowledge of human ity might be a more effective treatment in this physiology well beyond fibromyalgia. Scientists cohort, but such an evaluation of comorbidity are discovering the nature of autonomic regula- was not a consideration in the pregabalin study.
tion and its varied impact on human function Of course, all of these studies require valida- unrelated to pain and fatigue. Central limbic tion through larger and longer trials but, unlike system influence on behavior, autonomic func- most medical challenges, future research must tion, analysis of pain transmission and receptor be rigorous indeed to overcome the emotionally dynamics are expanding our basic knowledge charged and controversial nature of fibromyal- of the CNS and suggesting novel applications gia. Yet while the challenge remains daunting, for many drugs currently used for a variety of the potential application of eventual discoveries seems almost limitless. Even this modest success Future fibromyalgia studies may begin to will be infectious. Interest in fibromyalgia consider the impact of comorbidities on thera- research and acceptance of fibromyalgia as a peutic outcome results. Exclusion criteria may genuine entity is expanding. As clinicians become much more important after we begin finally see meaningful clinical improvement to understand the mechanisms of action of and even recovery, an explosive potential these new medications. Just as diet affects insu- emerges to encourage greater dedication to lin response in diabetics and multiple risk fac- finally solving the fibromyalgia problem for tors affect long-term outcomes in patients and clinicians alike.
cardiovascular trials, the same is true forcomorbidities with fibromyalgia. Untreated Information resources obstructive sleep apnea was excluded in thepramipexole and ropinirole trials and added as • Fibromylagia clinical trials an exclusion criterion in a new sodium oxybate trial. Theoretically, the profound autonomic (Accessed October 2005) Women's Health (2005) 1(3)
Treatment of fibromyalgia – REVIEW Executive summary
• Fibromyalgia syndrome (FMS) is a specific musculoskeletal condition affecting 10 million Americans validated by specific criteria published by the American College of Rheumatology in 1990.
• Diagnosis is based on demonstration of widespread pain for at least 3 months and specific tenderness to gentle palpation symmetrically at tender points.
• FMS tender points are located at the occiput, trapezius, medial clavicle, lateral epicondyle, sacroiliac, greater trochanteric and medial knee regions.
• FMS is not a diagnosis of exclusion and important comorbid pain can complicate the presentation and require independent diagnosis and treatment.
• FMS symptoms have been reproduced after auditory fragmentation of stage III/IV sleep for 4 nights.
• Similar experiments in athletes and disruption of rapid eye movement (REM) sleep did not lead to FMS symptoms.
• Pain and tenderness have been attributed to amplified central pain processing, but the specific mechanism has not yet been identified.
• Abnormal regulation of autonomic control is a prominent feature of FMS and may explain the strong association of irritable bowel syndrome, irritable bladder, palpitations and vasomotor instability with FMS.
• Inadequate hippocampal attenuation of autonomic arousal fragmenting sleep appears to be a fundamental feature of FMS.
• Dopaminergic control of hippocampal function suggests a novel treatment approach to FMS.
Traditional treatment options
• Exercise, usually aerobic and carefully graded, consistently reduces FMS symptoms for some patients, but fails to address FMS pathogenesis.
• Controlled trials with acupuncture, massage, ultrasound, mineral baths and cognitive behavioral therapy demonstrate 30% reduced pain.
• Fluoxetine (20 mg), amitriptyline (25 mg), sertraline (50 mg), cyclobenzaprine (1–30 mg), tizanidine (4–24 mg), carisoprodol (1200 mg) and temazepam (15–30 mg) demonstrated a clinical benefit in controlled trials.
• Ibuprofen (2400 mg), naproxen (1000 mg), prednisone (15 mg) and alprazolam (0.5–3.0 mg) failed to benefit FMS patients in controlled trials. Zolpidem (5–15 mg) improved sleep, but not FMS pain.
• Pregabalin, a precursor of gabapentin, is a ligand for α2-δ subtype 1 and 2 receptors affecting CNS voltage-gated calcium channels.
• In the largest FMS trial to date (528 patients), pregabalin (450 mg) significantly reduced FMS pain over 8 weeks.
• A total of 29% of patients receiving pregabalin achieved more than 50% decreased pain compared with 11% receiving placebo.
• Milnacipran and duloxetine are mixed 5-hydroxytryptamine (5-HT) and norepinepherine reuptake inhibitors (SNRI) indicated for the treatment of depression.
• In a Phase II trial, 37% of patients with FMS receiving milnacipran noted a greater than 50% pain reduction compared with 14% receiving placebo. Adverse events were unremarkable.
• In two large trials, duloxetine did not reduce pain in men, but effectively reduced many FMS symptoms, including pain, in women. In the first trial, including men, 28% receiving duloxetine noted greater than 50% decreased pain compared with 17% receiving placebo.
Stage IV sleep induction approach
• Sodium oxybate induces stage IV sleep and is a commercial form of g-hydroxybutyrate (GHB), a naturally occurring CNS metabolite. It is indicated for the treatment of narcolepsy in patients with cataplexy.
• In a pilot controlled trial in 24 patients, sodium oxybate significantly increased stage IV sleep duration, decreased arousals fragmenting sleep and reduced FMS pain and fatigue by 29–33%.
Dopamine agonist approach
• Ropinirole and pramipexole are selective dopamine D3 receptor agonists developed for the treatment of Parkinson's disease and commonly used for the treatment of restless legs syndrome.
REVIEW – Holman Executive summary (Cont.)
• Much higher doses demonstrate efficacy for FMS when given at bedtime. Typical dopamine intolerances, including nausea, are noted and often require concomitant treatment.
• In a pilot trial in 30 patients, ropinirole (8 mg) safely reduced pain without achieving statistical significance. A large European study at higher doses has just been completed.
• Over 14 weeks, 42% of patients receiving pramipexole (4.5 mg at bedtime) noted more than 50% decreased pain compared with 14% receiving placebo. Significant improvements in fatigue, function and global assessment were also noted.
• The most common adverse events were mild nausea and weight loss in the pramipexole arm and nausea and weight gain in the placebo arm.
• Identifying the role of autonomic regulation of sleep stage architecture, the importance of hippocampal control of autonomic arousal and the mechanism of central amplified pain will be central themes.
• Combination therapy with these varied treatment approaches to FMS and identifying the influence of comorbidities will make the treatment of FMS more complex, but also more successful.
Important paper demonstrating the
Turk DC: The potential of treatment Papers of special note have been highlighted as importance of sleep stage architecture
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fibromyalgia. Ann. Intern. Med. 143(1), 124 syndrome): a parallel double-blind trial Fundamentally important paper
with carisoprodol, paracetamol and introducing a new treatment concept.
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of addressing serotonin and
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norepinepherine in FMS drug development.
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central alpha-2- agonist (tizanidine) WB Saunders Co., Philadelphia, PA, USA, Important paper describing a new approach
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REVIEW – Holman Wernicke JF, Rosen AS, Lu Y et al.: Holman AJ: Treatment of fibromyalgia with Conference on Functional Mapping of the Duloxetine in the treatment of fibromyalgia. the dopamine agonist ropinirole: a 14-week Human Brain. Poster TU 342 (Abstract).
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trial with 14-week blinded extension. Fredrickson PA: Effect of pramipexole in Important example of how redesign of a
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during sleep: comparisons of clinical features First report describing this new approach
and sleep parameters. Sleep 19(3), 200–204 per describing restless legs
syndrome in FMS.
Holman AJ, Neiman RA, Ettlinger RE: Exceptional paper explaining important
Lopez JF, Akil H, Watson SJ: Neural circuits Preliminary efficacy of the dopamine sleep issues in FMS.
mediating stress. Biol. Psychiatry 46(11), agonist, pramipexole for fibromyalgia: the Roizenblatt S, Moldofsky H, Benedito-Silva 1461–1471 (1999).
first, open label, multicenter experience. AA, Tufik S: Alpha sleep characteristics in Wood PB: Fibromyalgia syndrome: a central J. Musculoskelet. Pain 12(1), 69–74 (2004).
fibromyalgia. Arthritis Rheum. 44(1), role for the hippocampus – a theoretical Holman AJ, Myers RR: A randomized, 222–230 (2001).
construct. J. Musculoskelet. Pain 12(1), double-blind, placebo-controlled trial of Exceptional paper explaining important
19–26 (2004).
pramipexole, a dopamine agonist, in sleep issues in FMS.
Critically important paper for those
patients with fibromyalgia receiving Scharf MB, Baumann M, Berkowitz DV: interested in FMS pathogenesis.
concomitant medications. Arthritis Rheum. The effects of sodium oxybate on clinical Wood PB, Hill AL, Featherstone L, 52(8), 2495–2505 (2005).
symptoms and sleep patterns in patients Patterson JP: Hippocampal metabolite Important paper describing a new
with fibromyalgia. J. Rheumatol. 30, abnormalities in fibromyalgia and their approach to FMS.
1070–1074 (2003).
symptom correlates. J. Musculoskelet. Pain Important paper describing a new
12, S73 (2004) (Abstract).
approach to FMS.
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Proceedings of the 10th International Women's Health (2005) 1(3)

Source: http://www.fms-wsm.org/pdf/fibromyalgia_treatment.pdf


NIH Public AccessAuthor ManuscriptSens Actuators B Chem. Author manuscript; available in PMC 2013 March 25. NIH-PA Author Manuscript Published in final edited form as: Sens Actuators B Chem. 2011 May 20; 154(1): 22–27. doi:10.1016/j.snb.2010.03.067. A microfluidic platform for electrical detection of DNA M. Javanmard* and R.W. DavisStanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, United States


The diabetic foot infection can lead to tissue necrosis and amputation. Diabetes is the leading non-traumatic cause of major amputation of the lower limbs. Miles J levyJonathan ValabhjiQ2 NeuropathyNerve damage due to disease of the vasa nervorum results in a ‘glove and stocking' sensorimotor peripheral neuropathy that may progress proximally. The motor component results in dener-vation of the small muscles of the foot, leading to: • hyperextension at the metatarsophalangeal joints