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8 Articles in Volume 6, Issue #6
Choosing and Using a Low Level Laser in Pain Management
Clinical Bioethics
Cranial Electrotherapy Stimulation in the Treatment of Fibromyalgia
Fibromyalgia: New Hope and New Pharmaceuticals
Identifica tion and Management of Cardiac -Adrenal-Pain Syndrome
Interventional Therapy
Superior Pharyngeal Constrictor Muscle Pain
Treating Neuropathic Pain in Multiple Sclerosis (MS)

Fibromyalgia: New Hope and New Pharmaceuticals

While few therapies have proven effective in the past, recent pharmacologic advances provide new hope for this difficult-to-treat disorder.

Fibromyalgia may produce pain ranging from mild to severe and is now among the major reasons for referral to a pain center. Until now, few therapies have proven effective but several new agents provide pain relief in most cases. This update reviews both the old and new pharmacologic agents used to treat fibromyalgia.

Despite the introduction of the term fibrositis in 1904 by Gower,1 progress in understanding FMS has been slow. However, recent innovative strategies and broader investigation of its cause, beyond a myopic focus on psychiatric or musculoskeletal research, have finally led to a new expectation of improved treatment outcome.

Firm confidence in a diagnosis is essential before formulating and implementing an effective treatment strategy in any medical condition. For many clinicians, the diagnosis of FMS remains confusing despite validated criteria published by the American College of Rheumatology in 1990 (See Table 1).2 While specific tenderness, or tender points, have been promoted as diagnostic evidence of this disorder, honest debate and, at times, unruly skepticism, is evident even among rheumatologists. While helpful as inclusion criteria for research studies, fibromyalgia tender-point intensity can still vary from day to day in clinical practice, leading to diagnostic uncertainty. Nevertheless, clinicians can readily recognize and attempt to treat the common presentation of chronic, unexplained, widespread pain, tenderness, and fatigue of fibromyalgia.

Table 1. The 1990 American College of Rheumatology Criteria for the Classification of Fibromyalgia2

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 pan 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 upper surfaces
  • 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.

Clinical Characteristics

  • 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 gently 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.

Pathogenesis

  • 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, palpations 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.

Etiology

There is no consensus regarding pathogenesis, but an abnormality of centrally mediated pain processing has gained greater acceptance.3 Functional magnetic resonance imaging (fMRI)4 and pain-testing studies5 have significantly strengthened this concept of centrally amplified pain perception. Observations of abnormal sleep-stage architecture6 and induction of FMS symptoms with specific disruption of deep, non-rapid eye movement (nREM), stage IV sleep,7 have encouraged consideration of how sleep affects a variety of CNS functions influencing pain, fatigue and cognitive behavior. Sophisticated measurements of autoimmune regulation with validated tools, including heart rate variability and tilt-table testing, have increased the awareness that patients with FMS fail to maintain normal sympathetic homeostasis.8-14 In turn, perturbed sleep, psychiatric arousal (e.g., post-traumatic stress disorder, bipolar disorder and anxiety disorder), peripheral vasomotor tone, cardiac rhythm, and bowel motility focus future research directly on new autonomic mechanisms that may lead to an improved understanding of FMS.

Clinical Presentation

Almost 85% of FMS cases occur in women, but men are often undiagnosed. In fact, the divergent presentation of FMS in men compared with women has been well reported.15 Pain and muscular spasm are generally more diffuse and vague in men. It appears that the hallmark diagnostic finding in FMS, 11 of 18 specific tender points, becomes apparent to the clinician and male patients much later in its clinical course. Response rates (RRs) to a variety of pharmacologic options are also less robust in men. The cause of these gender differences in presentation and response is uncertain, but may relate to behavioral differences, comorbidities, or hormonal variations, including clinically amenable testosterone deficiency in men receiving chronic opioids.

The variability and unpredictability of treatment response has fueled clinician skepticism regarding FMS as a specific disorder, and gender differences also enhance this debate. Some explain this paradox by considering FMS as a family of disorders and suggest defining FMS subsets to improve treatment outcomes for specific medications.16 Unfortunately, the importance of comorbidities accompanying FMS and interfering with the treatment response has been given little consideration. Due to the general vagueness of fatigue and widespread pain as symptoms, most clinicians find teasing apart comorbidities particularly difficult in patients with FMS. Nevertheless, defining all accompanying causes of pain when treating FMS, such as arthritis, myelopathy, bursitis, tendonitis, and migraine to name a few, is as important as identifying all risk factors for cardiovascular disease.

Pain and tenderness should be widespread in all four limbs and the axial spine. FMS is not a diagnosis of exclusion One must be confident of the diagnosis and even more aware of comorbidities before considering treatment or evaluating a treatment response. Effective treatment of other causes of pain such as stress, insomnia, and autoimmune dysfunction are equally important to the overall outcome as the choice of treatment for FMS.

Traditional Treatment

Treatment of FMS has been effectively reviewed over the past few years, but some authors tend to favor more traditional approaches.17 Until the “magic bullet” is discovered, a balanced and comprehensive approach appears reasonable since these modalities have sometimes provided a benefit. Even among nonbelievers, most clinicians encourage exercise for patients with FMS. In 1988, a randomized trial of exercise demonstrated improvement in FMS pain threshold compared with flexibility training after 20 weeks.18 Aerobic exercise,19 muscle strengthening, pool exercises20 and spa therapy21 have been found to be helpful. Many studies supportive of exercise vary in methodology and have significant limitations, including inadequate blinding and small sample size.

However, a thorough review by Goldenberg and colleagues concluded that all patients with FMS should begin a cardiovascular program.22

Analysis of these exercise studies reveals important limitations, including appropriate matching of specific therapies with heterogeneous patients and consistent adherence to exercise regimens.23 In addition, while statistical significance was routinely achieved, the magnitude of the benefit (25-30% improvement) would not be considered robust. Most clinicians note that many of their patients with FMS fail to respond to exercise and many decline, or are unable to participate in such structured programs implemented at an experienced research facility. Regrettably, outcomes from many exercise trials simply do not translate into clinical practice.

The notion of exercise as an effective therapeutic option for FMS may have arisen from the observation that aerobic fitness may be preventative. In 1975, Moldofsky induced widespread pain suggestive of FMS by disrupting stage IV sleep with an auditory arousal for four nights in healthy college students.6 Similar results did not occur when he repeated the experiment in fit military recruits or after disruption of REM sleep stages.7 It is not clear how fitness preserves the benefits of stage IV sleep, but incorporation of aerobic exercise into an FMS treatment strategy remains popular.

Evidence that other nonpharmacologic remedies are effective is debatable, yet accepted by many clinicians. Soft-tissue injection with saline, local anesthetics and/or corticosteroids have been offered to patients with FMS, but placebo-controlled trials are unavailable. Acupuncture may reduce pain and analgesic requirements but, of three controlled studies,24-26 only one demonstrated a significant treatment benefit compared with placebo. Massage,27 ultrasound,28 and mineral baths29 demonstrate a benefit for pain compared with placebo, but sustained meaningful improvement is unusual. Cognitive behavioral therapy has become a logical and helpful therapeutic approach for FMS,30 but many patients lack access to skilled therapists.

In 2004, Goldenberg and colleagues provided an evidence-based review of FMS management.22

Their assessment of FMS studies based on study size, design, and reproducibility is clearly the most thorough review of traditional treatment options for FMS to date. The greatest improvement in pain as an outcome variable compared with placebo was also reported by Goldenberg in 1996 in a study of fluoxetine (20mg each morning) combined with amitriptyline (25mg at bedtime).31 In this four-arm, 6-week, double-blind, crossover study, fluoxetine alone and amitriptyline alone improved pain and global function, but not fatigue or tender-point score. Combined, in the fourth arm, improvement in pain and fibromyalgia impact questionnaire (FIQ) scores improved maximally (34%). Other studies with amitriptyline alone have confirmed a statistically significant decrease in FMS pain of approximately 30%.32 Uncontrolled reports of serotonin (5-hydroxytryptamine (5-HT)) reuptake inhibitors, including sertraline,33 also suggest modest efficacy.

The second most frequently studied drug class for the treatment of FMS are the muscle relaxants, including cyclobenzaprine. Dosed at 10-30mg at bedtime, a meta-analysis of randomized studies demonstrated a benefit similar to amitriptyline.34 Even doses as low as 1-4mg at bedtime have demonstrated some analgesic efficacy and improved sleep stage architecture.35 Decreased levels of cerebrospinal fluid (CSF) neuroamines and substance P were reported by Russell with tizanidine 4-24mg each day.36 Carisoprodol dosed at 1200mg/day decreased FMS pain compared with placebo in one study,37 but this result has not been confirmed. Other muscle relaxants are routinely used by clinicians without literature support.

Other classes of medication available to treat FMS have not demonstrated efficacy compared with placebo, including ibuprofen (2400mg/day for 3 weeks).38 naproxen (1000mg/day for 6 weeks)39 or prednisone (15mg/day for 2 weeks).40 Temazepam (15-30mg at bedtime for 12 weeks) demonstrated a modest statistical benefit,41 but alprazolam (0.5-3.0mg at bedtime) was not superior to placebo.42 Finally, a randomized 13-week trial of tramadol in combination with acetaminophen in 315 subjects demonstrated significant analgesic efficacy without any serious adverse effects.43

A controlled trial of zolpidem (Ambien®, Sanofi-Synthelabo) may provide an important illustrative example. As a sedative hypnotic, zolpidem induces stage II rather than stage IV sleep. Subjects noted improved sleep duration and decreased sleep latency, but did not note improved FMS pain or fatigue compared with subjects receiving placebo.44 Perhaps, if the medication effectively restored depleted stage IV sleep, an improvement in FMS symptoms may have been found.

Finally, although controlled trials are unavailable, the safety of clonazepam and lorazepam in 160 patients over 12 months was encouraging.45 Patients did not escalate their bedtime dose (2.0mg) or note significant adverse events, including withdrawal seizures. Contrary to other benzodiazepines, lorazepam and clonazepam effectively reduce restless legs syndrome (RLS) symptoms,46 a common source of arousal fragmenting sleep quality in patients with FMS.

New Pharmacologic Treatment Options

Research in fibromyalgia has grown exponentially and new, meaningful treatment options are now at hand. Every clinician brave enough to accept patients with FMS recognizes many obstacles that interfere with successful treatment. However, embracing a team approach, identification of important comorbidities, and consideration of novel medications are improving outcomes. In addition, large pharmaceutical companies are engaged in a race to discover an effective treatment. A list of promising new therapies for FMS include the following:

  • Pregabalin (Lyrica™, Pfizer)
  • Milnacipran (Dalcipran®, Cypress Bioscience)
  • Duloxetine (Cymbalta®, Eli Lilly)
  • Sodium oxybate (Xyrem®, Orphan Medical/Jazz Pharmaceuticals) and the dopamine agonists
  • Ropinirole (Requip®, G1axoSmithKline)
  • Pramipexole (Mirapex®, Boehringer- Ingelheim)

Pregabalin

In one of the largest controlled trial for FMS to date with 528 patients, pregabalin demonstrated significant improvement in pain score, sleep quality, fatigue and global measures of change.47 Pregabalin—a precursor of gabapentin (Neurontin®, Pfizer)—has analgesic, anxiolytic, and antiepileptic effects in animals. It is a ligand for a2-S subtype 1 and 2 receptors that adheres to voltage-gated calcium channels without affecting g-aminobutyric acid (GABA) receptors.48 Its activity is limited to neurons and it does not affect vascular calcium channels. Reduction of calcium influx at the neuron reduces release of substance P, glutamate and norepinepherine (NE),49 which is thought to mediate its analgesic and anxiolytic actions.

Subjects were assigned (1:1:1:1) to placebo or one of three pregabalin doses (150, 300 or 450mg/day) for eight weeks. Demographics for each group were similar, including 90% women, 95% Caucasian, with an FMS duration of eight years and mean pain score of 7 (range: 1 [no pain] - 11 [worst pain]). Patients discontinued prior medications and 77% completed the trial. All active arms improved within approximately two weeks and demonstrated sustained improvement through to week eight. Treatment with pregabalin was associated with statistically significant dose-dependent improvement. However, improvement in pain score was modest, even in the 450mg arm (-0.93, 1-11 scale), and the p-value (p=0.0009) reflected the large size of the study. Adverse events were common but mild and transient, including dose-dependent dizziness (49% in the 450mg arm vs. 11% for placebo). Somnolence (28%), dry mouth (13%), peripheral edema (11%), and weight gain (7%) were also more common with pregabalin than placebo.

“Every clinician brave enough to accept patients with FMS recognizes many obstacles that interfere with successful treatment. However, embracing a team approach, identification of important comorbidities, and consideration of novel medications are improving outcomes.”

Pregabalin represents an extension of the neuropathic/anticonvulsant therapeutic approach to FMS. While psychiatric medications have been the mainstay of FMS pharmacopeia, many pain centers have addressed pain, and FMS specifically, as a neuropathic pain.50 Narcotic analgesic efficacy for FMS has been mixed,51 but anticonvulsant medications have become very popular based on anecdotal evidence. In fact, off-label use of gabapentin has been so widespread in North America that the U.S. Food and Drug Administration (FDA) fined its original manufacturer, Warner-Lambert (Parke-Davis Division, New Jersey), for promoting unapproved uses (www.FDA.gov). To date, there are no FDA-approved medications indicated for the treatment of FMS, and evaluation of innovative off-label FMS therapies has become more difficult in the United States following this reprimand.

Milnacipran

The dual 5-HT and NE reuptake inhibitors (SNRIs) have received widespread attention as the next breakthrough for patients with FMS. While a controlled study of venlafaxine (Effexor®, Wyeth) was inconclusive,52 two case reports suggested a significant benefit at higher dosage.53,54 Milnacipran, a popular antidepressant in Japan, is a novel SNRI that favors reuptake inhibition of NE over 5-HT. Reduction of pain in a variety of animal models may be related to the roles of NE and 5-HT in pain-modulating systems via the descending inhibitory pathways in the brain and spinal cord.55 Tricyclic antidepressants mediate pain through 5-HT and NE neurotransmission and reduce FMS pain. This potential mechanism of pain amplification supports the consideration of SNRIs, which may be better tolerated than tricyclics, for the treatment of FMS.

In a 12-week, double-blind, placebo controlled Phase II trial, 125 patients with FMS were randomized (3:3:2) to receive milnacipran once or twice daily (up to 200mg/day) or placebo.56 RR was defined as the percentage of subjects who achieved a 50% or greater pain reduction by visual analog scale on an electronic diary. For this outcome milestone, the intention-to-treat (ITT) analysis RR for twice daily dosing was 37%, 22% for once daily, and 14% for placebo. Only the twice-daily dose response was statistically superior to placebo (p=0.04), but both twice and once daily outcomes on a secondary efficacy measure, the patient global impression of change (PGIC), were superior to placebo (p=0.003). Multiple components of the FIQ and the short-form McGill pain questionnaire (SF-MPQ) also showed statistically significant superiority over placebo for both the once- and twice-daily dosing arms.

Adverse events were unremarkable. A Phase III trial has been completed, but details have not yet been reported. However, data discovered by investors and briefly discussed by Cypress Bioscience suggest that their study barely failed to achieve a statistically positive outcome despite enrolling over 800 subjects (P=0.06). This news lead to a sudden 40% drop in the share price of Cypress Bioscience in September 2005, but its partner, Forest Pharmaceutics, has decided to continue development with redesigned studies and different primary outcomes. Milnacipran is not yet available in the USA, but this focus on SNRIs and the role of 5-HT and NE in pain modulation, and for FMS specifically, represents a hopeful and increasingly popular approach.

Duloxetine

Two large controlled trials of duloxetine have been recently reported in patients with FMS, demonstrating interesting results. Duloxetine is a SNRI approved by the FDA in 2005 for the treatment of major depressive disorder and neuropathic pain associated with diabetic peripheral neuropathy. Its inhibition of 5-HT and NE reuptake is relatively balanced without interacting with opioid, muscarinic, histamine-1, a-adrenergic, dop-amine, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A and 5-HT3C receptors. Once again, in animal models, this SNRI reduced pain behavior and did so with greater potency than venlafaxine, amitriptyline or desipramine.

These two trials illustrate important issues in FMS research. The first trial, reported in 2003, randomized (1:1) 207 subjects to duloxetine 60mg twice daily for 12 weeks or placebo.57 Demographic variables were equally distributed in the two arms and included 87% women (85% Caucasian), with 38% having major depression. The coprimary outcomes were FIQ total score (0-80) and FIQ pain subscore (0 [no pain]-10 [severe pain]).

Compared with placebo, duloxetine reduced total FIQ significantly (-5.53, 95% confidence interval [95% CI]: -10.43,-0.63 [p=0.027]), but did not reduce the FIQ pain subscore (p=0.13). Many other secondary measures of pain were found to be statistically improved, including the brief pain inventory (BPI), PGIC, number of tender points, FIQ stiffness subscore, and several quality of life measures. A subanalysis revealed that men with FMS failed to respond to duloxetine, and that comorbid depression did not influence FMS treatment response. Reported adverse events were typical of SNRI therapy and included insomnia, dry mouth, and constipation more frequently than placebo. Duloxetine intolerance was mild-to-moderate and did not lead to significant withdrawal from the study.

The study was repeated with the exclusion of men, the primary outcome was changed, and the sample enlarged to favor a statistically significant treatment response.58 The FIQ became a secondary outcome measure and the BPI became the primary outcome. In this new 12-week study, 354 women with FMS were randomized (1:1:1) to receive duloxetine 60mg daily, 60mg twice daily or placebo. Pain decreased significantly in subjects treated with duloxetine (daily and twice daily) compared with placebo (p<0.001), as assessed by the BPI. RR was defined as a 30% (rather than 50%) reduction in pain and was achieved by 55% in the daily arm, 54% in the twice-daily arm, and by 33% in the placebo arm. The size of the study ensured that these differences were statistically significant. The authors’ conclusion, that duloxetine is an efficacious and safe treatment for FMS, is not unreasonable. However, scrutiny of the two study designs, including exclusion of nonresponders (men) and changing to a more favorable outcome variable emphasizes the importance of careful review of study design.

Sodium Oxybate

A third treatment approach for FMS focuses directly on sleep physiology and is based on the importance of a-wave fragmentation of stage IV sleep more than on SNRI- or anticonvulsant-mediated modulation of pain neurotransmission. Diminished slow-wave sleep has been identified as an important feature in FMS and different types of a-wave intrusion of stage IV sleep have been identified.59,60 Sodium oxybate is a commercially available form of g-hydroxybuyrate (GHB), a naturally occurring CNS metabolite primarily found in the hippocampus and basal ganglia. It is the only compound known to increase growth hormone secretion and deep, slow-wave stage IV sleep and is FDA approved for the treatment of cataplexy in patients with narcolepsy.

A double-blind, crossover trial of sodium oxybate in 24 patients was conducted over 1 month intervals with a 2-week washout period.61 A total of 18 subjects completed the trial of sodium oxybate (6.0mg at bedtime) compared with placebo and were monitored by polysomnogram (PSG), tender-point index and subjective measurements of improvement in daily diaries. A variety of pain and fatigue scores improved by 29-33% in the active arm compared with 6-10% in the placebo arm (p<0.005). Tender-point score decreased by 8.4 points with sodium oxybate compared with an increase of 0.4 points in the placebo arm (p=0.008). PSG measures of inappropriate CNS arousal, including a-wave intrusion, sleep latency and ‘REM decreased with treatment, while stage III and IV slow-wave sleep increased compared with placebo (p<0.005).

This study provided preliminary yet compelling evidence that FMS pain and fatigue improve with increased slow-wave sleep and decreased a-wave intrusion. A larger, multicenter, controlled study was reported at the 2005 annual meeting of the American College of Rheumatology. In this 8-week, placebo controlled Phase II trial, subjects were randomized (1:1:1) to placebo, 4.5 gm or 6.0 gm of sodium oxybate. Their primary outcome was a triple composite, including simultaneous 20% improvement in FIQ, 20% improvement in 10 cm VAS pain score and ‘much better’ or ‘very much better’ on Patient Global Impression of Change (PGIC). More subjects in the active arms achieved this level of treatment response than those in the placebo arm (placebo 17% , 4.5 gm 35% [p=0.005], 6.0 gm 27%, [p=0.05]).62

The therapeutic role of restoring stage IV deep sleep to address FMS symptoms provides another important approach quite different from treating FMS with analgesics, anticonvulsants, or SNRIs. Based on Moldofsky’s landmark sleep deprivation studies6,7 and these sodium oxybate results, a renewed emphasis on the restoration of normal sleep-stage architecture has gained more attention as a primary, rather than secondary, therapeutic goal.

Ropinirole

Most FMS reviews do not mention dopamine agonists (e.g., ropinirole and pramipexole), as initial reports were anecdotal until late 2004. These medications were FDA-approved for the treatment of Parkinson’s disease in 1997 and the reasoning behind their use is far afield of traditional approaches to FMS. Ropinirole is a dopamine receptor agonist with specificity for the dopamine 2 and 3 subreceptors (D2, D3). It is metabolized in the liver by the cytochrome P450 (CYP)C1A isoenzyme and has negligible affinity for muscarinic, acetylcholine, adrenergic, opioid, or 5-HT receptors.

In 2003, the first use of ropinirole for the treatment of FMS was reported in an open-label assessment of 17 patients who noted a 64% decrease in tender-point pain score over 4 months at a mean dose of 6.0mg at bedtime.63 While the approved maximum dose for RLS is 4.0mg at bedtime, the typical dose for Parkinson’s disease is 1-8mg orally three times daily. In 2004, in a controlled trial of 30 patients with FMS,64 20 patients were randomized to ropinirole and 10 were assigned to the placebo arm. Ropinirole was gradually increased over 14 weeks to 8mg at bedtime. Although 45% of patients receiving ropinirole achieved a 50% or greater reduction in 10 cm visual analog pain score compared with 30% of placebo patients, the results of this small, pilot study were not statistically significant (p=0.31). All other measures of efficacy (tenderness, fatigue and function) also showed a trend towards the efficacy of ropinirole compared with placebo.

The most common adverse events were typical intolerances seen with dopaminergic therapy, including mild-to-moderate nausea. Interestingly, sudden, uncontrolled daytime sleepiness (sleep attacks) as well as orthostatic hypotension, experienced by patients with Parkinson’s disease treated with daily dopamine agonists, were not seen in this FMS trial.

Table 2. Comparison of Treatments/Medications for Fibromyalgia
 

Traditional Approaches

  • 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 demonstrates 30% reduced pain.
  • Fluoxetine (20mg), amitriptyline (25mg), sertraline (50mg), cyclobenzaprine (1-30mg), tizanidine (4-24mg), carisoprodol (1200mg) and temazepam (15-30mg), demonstrated a modest clinical benefit in controlled trials.
  • Ibuprofen (2400mg), naproxen (1000mg), prednisone (15mg) and alprazolam (0.5-3.0mg) failed to benefit FMS patients in controlled trials. Zolpidem (5-15mg) improved sleep, but not FMS pain.

Neuropathic Approach

  • Pregabalin, a precursor of gabapentin, is a ligand for a2-d subtype 1 and 2 receptors affecting CNS voltage-gated.
  • In 528 patients, pregabalin (450mg) 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.

Psychiatric Approach

  • 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 d-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. Both show promise for treatment of FMS with pramipexole demonstrating the highest pain response to date.

Recently, a controlled FMS trial with a new extended-release ropinirole formulation dosed at bedtime was completed in Europe. While subjects were expected to receive 16-24mg of extended-release ropinirole at the discretion of their investigator, the mean treatment dose was only 8.2mg qd. This dose correlates with approximately 3mg of immediate release ropinirole. This inadequate dosing scheme may have contributed to it failure to demonstrate a statistically significant treatment effect.65

Nevertheless, the rationale for using a dopamine agonist begins with a greater appreciation of the higher incidence of RLS in patients with FMS (31%) compared with normal controls (3%).66 In May 2005, ropinirole became the first medication approved for the treatment of RLS by the FDA.

This RLS arousal inhibits deep sleep and ties in with the Moldofsky findings. While sedating medications are commonly offered to promote deep sleep by overwhelming arousal in FMS, the dopamine agonist was intended to reduce arousal fragmenting normal sleep.

Interestingly, dopamine agonists are not sedating and their mechanism of action in FMS is under investigation. Abnormal sympathetic arousal has been documented in FMS, and these patients maintain poor autonomic homeostasis. Excessive fight-or-flight responses as well as specific arousals such as intense chronic pain, frustration, post-traumatic stress disorder, and anxiety have been well documented in FMS. Any of these arousals can chronically disrupt deep, restorative sleep.

D3 receptors are primarily found in the limbic system, including the hippocampus, but not in the sympathetic arousal centers in the brainstem. The hippocampus attenuates and balances sympathetic arousal.67 Inadequate dopaminergic control of autonomic drive from the hippocampus has been suggested as a fundamental issue in FMS pathogenesis.68 In fact, preliminary magnetic resonance imaging (MRI) volumetric assessment has demonstrated hippocampal atrophy in patients with FMS compared with normal controls.69,70 Consequently, a medication capable of decreasing RLS and restoring normal hippocampal dampening of brainstem autonomic arousal would be a logical therapeutic option for FMS.

Pramipexole

Although pramipexole is indicated only for the treatment of Parkinson’s disease by the FDA, it also effectively reduces RLS.71 Its profile is similar to that of ropinirole, except that it is renally metabolized and has mild affinity for central adrenergic a2 receptors (the target of tizanidine and clonidine) in addition to D2 and D3 receptors.

Following two positive open-label reports,72,73 a controlled trial of pramipexole for FMS in 60 subjects (57 women, 3 men) was recently presented.74 Over 14 weeks, subjects were randomized (2:1) to a weekly fixed dose escalation of pramipexole from 0.25 to 4.5mg at bedtime or placebo. Significant reductions in visual analog pain, fatigue, total FIQ score, and global function at week 14 were found. The mean pain score decreased by 36% in the active arm compared with 9% for placebo by ITT analysis (p=0.008). A pain reduction of 50% or greater was seen in 42% of patients receiving pramipexole compared with 14% receiving placebo. All other secondary outcome measures trended better for the active arm, including tender-point index, Beck anxiety score, and Hamilton depression scale, without achieving statistical significance.

The most common adverse event was nausea, occurring in 79% of the active arm and 71% of the placebo arm. Nausea did not lead to discontinuation of pramipexole and was addressed by concomitant use of proton pump inhibitors. A mean weight gain of 3 lbs was seen in the placebo arm, while 40% of patients in the active arm noted 5-25 lb. weight loss at week 14 (p=0.001). Transient increased anxiety (14%) and vomiting (16%) were seen in the active arm but were not reported in the placebo arm. One episode of transient amnesia (<24h) required hospitalization for evaluation, but the patient fully recovered and completed the trial (double-blinded) six weeks later.

This study was very atypical for a FMS study. Subjects were allowed to maintain stable doses of other medications and psychiatric and pain comorbidities were allowed. A total of 53 of the 59 patients who completed the trial maintained stable doses of other medications, including 50% requiring daily narcotic analgesics. For any addition of a new medication during the study, the final untainted assessment was used as the final outcome. In addition, 30% of subjects were disabled, of whom one returned to work during the study (active arm).

Most FMS clinical trials only include patients without comorbidities who are willing to wash out all other medications and risk receiving a placebo for many months. This bias may affect interpretation of results and question the relevance of study conclusions for the clinician caring for patients with comorbidities and more severe FMS. It is unlikely that future pregabalin, milnacipran, sodium oxybate or ropinirole FMS trials will assess a similarly disabled and narcotic dependent FMS cohort, but perhaps a more traditional trial with pramipexole as monotherapy will be completed. Then, results from these different trials may be compared more fairly.

Conclusion

Potential new therapies for FMS from divergent approaches are developing at an unprecedented pace. A comparison of different treatments/medications is shown in Table 2. Scientific principles of FMS are becoming clearer as basic scientists study neuropharmacology and clinicians observe unexpected benefits and confirm them in randomized trials. Application of traditional, conservative treatments remain an option, but greater response rates have emerged with the use of medications capable of manipulating 5-HT, NE, and dopamine. As with any review of randomized trials, only longer and larger studies can confirm or refute these early findings. However, with these new developments, clinician can begin to have more confidence in their ability to improve the lives of patients with fibromyalgia.

Last updated on: May 16, 2011
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