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Referencias: Fibromialgia


Arnold LM, Russell IJ, Duan WR, et al. A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia. J Pain. 2008;9(9):792-805.

The purpose of the study was to assess the efficacy and safety of pregabalin monotherapy in patients with fibromyalgia in a randomized, double-blinded, placebo-controlled trial. After 1 week of single-blinded administration of placebo, 750 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to pregabalin (300 mg/d, 450 mg/d, 600 mg/d) or placebo, administered twice daily for 14 weeks. The primary outcome variable was comparison of end point mean pain scores, derived from daily diary ratings of pain intensity (0 to 10 scale), between each of the pregabalin groups and the placebo group. If positive, additional primary efficacy parameters included the Patient Global Impression of Change (PGIC) and the Fibromyalgia Impact Questionnaire (FIQ) total score. Compared with placebo-treated patients, mean changes in pain scores at the end point in pregabalin-treated patients were significantly greater (P < .001: 300 mg/d, -0.71; 450 mg/d, -0.98; 600 mg/d, -1.00). Compared with placebo, significantly more pregabalin-treated patients reported improvement on PGIC (P < .01 for all 3 pregabalin doses) and significant improvements in total FIQ score for the 450 mg/d (P = .004) and the 600 mg/d (P = .003) doses. Compared with placebo, all 3 doses of pregabalin were associated with significant improvement in sleep. The most commonly reported pregabalin-related adverse events were dizziness and somnolence, which tended to be dose-related.




Arnold LM, Sarzi-Puttini P, Arsenault P, et al. Efficacy and safety of pregabalin in patients with fibromyalgia and co-morbid depression receiving concurrent antidepressant therapy: a randomized, 2-way crossover, double-blind, placebo-controlled study. Presented at: 2013 American College of Rheumatology Annual Meeting; October 29,2013;San Diego, CA. Abstract #L6.

Background/Purpose: Fibromyalgia (FM) is characterized by chronic widespread pain and often associated with mood disorders including depression. Approximately 50–70% of FM patients have a lifetime history of co-morbid depression and ~25% have a history of antidepressant therapy. Pregabalin (PGB) is approved for the treatment of FM in the US, Japan and other countries. Because prior PGB FM clinical trials excluded the concomitant use of antidepressant medications, information about the efficacy and safety of adding PGB to antidepressant medications in patients with depression and FM is lacking.
Methods: This was a randomized, 2-way crossover, double-blind, placebo-controlled study of PGB in FM subjects with co-morbid depression receiving concurrent antidepressant medication for the treatment of depression with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Patients were aged ≥18 years, met the 1990 American College of Rheumatology criteria for FM, had a mean numeric rating scale (NRS) pain score of ≥4 (NRS scored from 0–10), a documented diagnosis of depression, and were being treated with a stable dose of a single SSRI or SNRI for the 2 months prior to randomization. All patients were randomized 1:1 to placebo or PGB (optimized to 300 or 450 mg/d) for the first 6-week treatment period (3 weeks dose optimization, 3 weeks fixed dose for each treatment period), and then switched to the alternate regimen for the second 6-week treatment period. Treatment periods were separated by a 2-week, single-blind taper/placebo washout. Stable antidepressant medication was continued throughout the study. The primary efficacy endpoint was mean pain score based on the mean of the last 7 daily pain scores.
Results: A total of 197 patients (93% female, 94% white, mean age 50 years) were randomized to treatment; 181 received ≥1 dose of treatment with PGB and 177 placebo. The mean time since diagnosis of depression was 12.3 years and the baseline mean Hospital Anxiety and Depression Scale – Depression score was 8.0, reflecting mild depression. At baseline, 52.3% were taking an SSRI, 47.7% an SNRI, and the mean pain score was 6.7. At the end of treatment, the least squares (LS) mean (SE) pain score was significantly lower with PGB (4.84 [0.15]) than with placebo (5.45 [0.16]) (LS mean difference -0.61; 95% confifidence interval -0.91 to -0.31; p=0.0001). Treatment emergent adverse events (AEs) were reported in 77.3% and 59.9% of patients receiving PGB and placebo, respectively. The most frequently reported AEs with PGB were dizziness (28.2%) and somnolence (19.9%). A total of 4 serious AEs were reported (3 with PGB and 1 with placebo), none of which were considered related to treatment. In patients receiving PGB, 6.1% discontinued treatment due to AEs, compared with 3.4% receiving placebo. Conclusion: PGB significantly improved FM pain in patients with FM and co-morbid depression receiving concurrent antidepressant medication, when compared with placebo. The safety profile of PGB in this population was consistent with previous studies and current product labeling.




Bohlega S, Alsaadi T, Amir A, et al. Guidelines for the pharmacological treatment of peripheral neuropathic pain: expert panel recommendations for the Middle East region. J Int Med Res. 2010;38(2):295-317.

Neuropathic pain (NeP) has been the focus of extensive basic and clinical research over the past 20 years. This has led to an increased understanding of underlying pathophysiological mechanisms and the development of new therapeutic agents, as well as a clearer definition of the role of established medications. To date there are no published treatment guidelines for NeP in the Middle East. A multidisciplinary panel of Middle East and international experts met to review critically and reach a consensus on how best to apply evidencebased guidelines for the treatment of NeP (mainly peripheral NeP) in the Middle East. The expert panel recommended pregabalin, gabapentin and secondary amine tricyclic antidepressants (nortriptyline and desipramine) as first-line treatments for peripheral NeP. Serotonin–norepinephrine reuptake inhibitor antidepressants, tramadol and controlled-release opioid analgesics were recommended as second-line treatments. There is a need to increase diagnostic awareness of NeP, use validated screening questionnaires and undertake more treatment research in the Middle East region.




Choy Ernest, RAes eparacht aireticnlet survey of the impact of fibromyalgia and the journey to diagnosis, Choy et al. BMC Health Services Research 2010, 10:102

Fibromyalgia is a painful, debilitating illness with a prevalence of 0.5-5.0% that affects women more than men. It has been shown that the diagnosis of fibromyalgia is associated with improved patient satisfaction and reduced healthcare utilization. This survey examined the patient journey to having their condition diagnosed and studied the impact of the condition on their life. Methods: A questionnaire survey of 800 patients with fibromyalgia and 1622 physicians in 6 European countries, Mexico and South Korea. Patients were recruited via their physician. Results: Over half the patients (61%) were aged 36-59 years, 84% were women, and the mean time since experiencing fibromyalgia symptoms was 6.5 years. Patients had experienced multiple fibromyalgia symptoms (mean of 7.3 out of 14), with pain, fatigue, sleeping problems and concentration difficulties being the most commonly reported. Most patients rated their chronic widespread pain as moderate or severe and fibromyalgia symptoms were on average "fairly" to "very" disruptive, and had a "moderate" to "strong" impact on patients' lives. 22% were unable to work and 25% were not able to work all the time because of their fibromyalgia. Patients waited on average almost a year after experiencing symptoms before presenting to a physician, and it took an average of 2.3 years and presenting to 3.7 different physicians before receiving a diagnosis of fibromyalgia. Patients rated receiving a diagnosis as somewhat difficult on average and had difficulties communicating their symptoms to the physician. Over one third (35%) felt their chronic widespread pain was not well managed by their current treatment. Conclusions: This survey provides further evidence that fibromyalgia is characterized by multiple symptoms and has a notable impact on quality of life and function. The diagnosis of fibromyalgia is delayed. Patients wait a significant period of time before presenting to a physician, adding to the prolonged time to diagnosis. Patients typically present with a multitude of symptoms, all resulting in a delay in diagnosis and eventual management. Helping clinicians to diagnose and manage patients with fibromyalgia should benefit both patients and funders of healthcare.




Clark P, Paiva ES. A patient and physician survey of fibromyalgia across Latin America and Europe. BMC Mulculoskelet Disord. 2013;14:188.doi:10.1186/1471-2474-14-188.

BACKGROUND: Patients and physicians from three Latin American (LA) and six European countries were surveyed in order to describe differences in journey to diagnosis, impact, and management of fibromyalgia (FM). METHODS: 900 patients (300 LA; 600 Europe) and 1824 physicians (604 LA; 1220 Europe) were surveyed between October-December 2010 (LA) and February-April 2008 (Europe). Patients and physicians (GP or specialists) completed separate questionnaires, on symptoms, impact, and FM management. Interviews were conducted in local languages. Appropriate rating scales were used throughout. Data were analyzed using cross-tabulations and descriptive statistics. Significance was determined at P<0.05 (indicated by *). RESULTS: In LA versus Europe, patients reported having FM symptoms for longer (100.8 vs. 83.7* months), and taking longer to be diagnosed (42.3 vs. 31.1* months). FM was characterized by multiple symptoms (11.2 vs. 6.9), but more LA patients reported 14 common symptoms*, and rated pain higher on 11-point scale (8.0 vs. 7.2*). LA patients were taking fewer medications (3.3 vs. 4.0). Patients from both regions found common symptoms very/extremely disruptive to their quality of life, but symptoms impacted daily living and ability to work more significantly in LA. Physicians (GPs or specialists) from LA more often considered problems sleeping*, difficulty concentrating*, anxiety*, depression*, numbness/tingling*, and leg cramps* very/extremely disruptive vs. European physicians. Despite headache, heightened sensitivity to touch, difficulty concentrating, and joint pain being experienced by ≥50% of patients from both regions, <15% of PCPs or specialists considered these typical FM symptoms. Patients also considered 12/14 symptoms more disruptive than PCPs or specialists in the same region. However, a higher proportion of PCPs or specialists considered FM to have a strong/very strong impact on aspects of daily living vs. patients within the same region. CONCLUSIONS: Patient- and physician-rated disease perception and impact was often higher in LA than in Europe. Patient and physician perspective concerning FM impact and disruption were often misaligned within the same region. Our observations may be representative of cultural differences in stoicism, expression, beliefs, and attitudes to pain perception and management. Better understanding of these complexities could help targeted educational/training programs incorporating cultural differences, to improve chronic care.




Crofford LJ, Mease PJ, Simpson SL, et al. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain. 2008;136(3):419-431.

This was a multicenter, double-blind (DB), placebo-controlled, randomized discontinuation trial to evaluate the efficacy of pregabalin monotherapy for durability of effect on fibromyalgia (FM) pain. The trial included a 6-week open-label (OL) pregabalin-treatment period followed by 26-week DB treatment with placebo or pregabalin. Adults with FM and 40-mm score on 100-mm pain visual analog scale (VAS) were eligible. During OL weeks 1-3, patients received escalating dosages of pregabalin to determine their optimal dosages. During OL weeks 4-6, patients received their optimal fixed dosages (300, 450, 600mg/d). To be randomized, patients must have had 50% decrease in pain VAS and a self-rating of "much" or "very much" improved on Patient Global Impression of Change (PGIC) at the end of OL. Double-blind treatment was with placebo or the patient's optimal fixed dosage of pregabalin. Primary outcome was time to loss of therapeutic response (LTR), defined as <30% reduction in pain (from OL baseline) or worsening of FM. A total of 1051 patients entered OL; 287 were randomized to placebo, 279 to pregabalin. Time to LTR was longer for pregabalin versus placebo (P<.0001). Kaplan-Meier estimates of time-to-event showed half the placebo group had LTR by Day 19; half the pregabalin group still had not lost response by trial end. At the end of DB, 174 (61%) placebo patients met LTR criteria versus 90 (32%) pregabalin patients. Pregabalin was well tolerated, though 178 (17%) discontinued during OL for treatment-related adverse events (AE), and more pregabalin than placebo patients discontinued for AEs during DB. In those who respond, pregabalin demonstrated durability of effect for relieving FM pain.
 




Gracely RH, Petzke F. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333-1343.

To use functional magnetic resonance imaging (fMRI) to evaluate the pattern of cerebral activation during the application of painful pressure and determine whether this pattern is augmented in patients with fibromyalgia (FM) compared with controls. METHODS: Pressure was applied to the left thumbnail beds of 16 right-handed patients with FM and 16 right-handed matched controls. Each FM patient underwent fMRI while moderately painful pressure was being applied. The functional activation patterns in FM patients were compared with those in controls, who were tested under 2 conditions: the "stimulus pressure control" condition, during which they received an amount of pressure similar to that delivered to patients, and the "subjective pain control" condition, during which the intensity of stimulation was increased to deliver a subjective level of pain similar to that experienced by patients. RESULTS: Stimulation with adequate pressure to cause similar pain in both groups resulted in 19 regions of increased regional cerebral blood flow in healthy controls and 12 significant regions in patients. Increased fMRI signal occurred in 7 regions common to both groups, and decreased signal was observed in 1 common region. In contrast, stimulation of controls with the same amount of pressure that caused pain in patients resulted in only 2 regions of increased signal, neither of which coincided with a region of activation in patients. Statistical comparison of the patient and control groups receiving similar stimulus pressures revealed 13 regions of greater activation in the patient group. In contrast, similar stimulus pressures produced only 1 region of greater activation in the control group. CONCLUSION: The fact that comparable subjectively painful conditions resulted in activation patterns that were similar in patients and controls, whereas similar pressures resulted in no common regions of activation and greater effects in patients, supports the hypothesis that FM is characterized by cortical or subcortical augmentation of pain processing.




Gracely RH, Petzke F. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333-1343.

OBJECTIVE: To use functional magnetic resonance imaging (fMRI) to evaluate the pattern of cerebral activation during the application of painful pressure and determine whether this pattern is augmented in patients with fibromyalgia (FM) compared with controls. METHODS: Pressure was applied to the left thumbnail beds of 16 right-handed patients with FM and 16 right-handed matched controls. Each FM patient underwent fMRI while moderately painful pressure was being applied. The functional activation patterns in FM patients were compared with those in controls, who were tested under 2 conditions: the "stimulus pressure control" condition, during which they received an amount of pressure similar to that delivered to patients, and the "subjective pain control" condition, during which the intensity of stimulation was increased to deliver a subjective level of pain similar to that experienced by patients. RESULTS: Stimulation with adequate pressure to cause similar pain in both groups resulted in 19 regions of increased regional cerebral blood flow in healthy controls and 12 significant regions in patients. Increased fMRI signal occurred in 7 regions common to both groups, and decreased signal was observed in 1 common region. In contrast, stimulation of controls with the same amount of pressure that caused pain in patients resulted in only 2 regions of increased signal, neither of which coincided with a region of activation in patients. Statistical comparison of the patient and control groups receiving similar stimulus pressures revealed 13 regions of greater activation in the patient group. In contrast, similar stimulus pressures produced only 1 region of greater activation in the control group. CONCLUSION: The fact that comparable subjectively painful conditions resulted in activation patterns that were similar in patients and controls, whereas similar pressures resulted in no common regions of activation and greater effects in patients, supports the hypothesis that FM is characterized by cortical or subcortical augmentation of pain processing.




Kavoussi R. Pregabalin: from molecule to medicine. Eur Psychopharmacol.c2006;16(suppl 2):S128-S133.

Pregabalin, a compound with a novel mechanism of action (MOA), has demonstrated efficacy as an adjunctive treatment for epilepsy and in several neuropathic pain models. Multiple generalized anxiety disorder (GAD) clinical trials have shown that pregabalin has efficacy similar to the benzodiazepines and venlafaxine. Onset of anxiolytic effect was observed as early as Week 1 of treatment, and efficacy was seen in treating both psychic and somatic anxiety symptoms. Pregabalin binds potently and selectively to the alpha-2-delta subunit of "hyper-excited" voltage-gated calcium channels (VGCCs). The binding of pregabalin to VGCCs changes their conformation, reducing calcium influx at nerve terminals. Pregabalin only modulates the release of excitatory neurotransmitters in "hyper-excited" neurons, restoring them to normal physiological state. This newly defined MOA is believed to confer on pregabalin its anxiolytic, analgesic, and anticonvulsant properties. Thus, pregabalin may offer physicians an effective and well-tolerated therapy for GAD, which differs from existing treatments.




Kim CH, Luedtke CA. Association of body mass index with symptom severity and quality of life in patients with fibromyalgia. Arthr Care Res. 2012;64(2):222-228.

OBJECTIVE: To examine the association between body mass index (BMI) and symptom severity and quality of life (QOL) in patients with fibromyalgia. METHODS: We assessed BMI status and its association with symptom severity and QOL in 888 patients with fibromyalgia who were seen in a fibromyalgia treatment program and who completed the Fibromyalgia Impact Questionnaire (FIQ) and the Short Form 36 (SF-36) health survey. RESULTS: The BMI distribution of nonobese (BMI <25.0 kg/m(2)), overweight (BMI 25.0-29.9 kg/m(2)), moderately obese (BMI 30.0-34.9 kg/m(2)), and severely obese (BMI ≥35.0 kg/m(2)) patients was 28.4% (n = 252), 26.8% (n = 238), 22.2% (n = 197), and 22.6% (n = 201), respectively. Age was significantly different among the 4 groups, with those having a greater BMI being older (P = 0.004). After adjustment for age, group differences were significant in the number of tender points (P = 0.003) and the FIQ and SF-36 scores. The groups with the greater BMI had greater fibromyalgia-related symptoms with worse FIQ total scores (P < 0.001), as well as worse scores in the FIQ subscales of physical function (P < 0.001), work missed (P = 0.04), job ability (P = 0.003), pain (P < 0.001), stiffness (P < 0.001), and depression (P = 0.03). These groups also had poorer SF-36 scores in physical functioning (P < 0.001), pain index (P = 0.005), general health perceptions (P = 0.003), role emotional (P = 0.04), and physical component summary (P < 0.001). Post hoc analysis among the 4 groups showed that differences resided primarily in the severely obese group compared with the other groups. CONCLUSION: In patients with fibromyalgia, severe obesity (BMI ≥35.0 kg/m(2)) is associated with higher levels of fibromyalgia symptoms and lower levels of QOL.




Lyseng-Williamson K, Siddiqui A. Pregabalin: a review of its use in fibromyalgia. Drugs. 2008;68(15):2205-2223.

Oral pregabalin, a calcium channel alpha(2)delta-subunit ligand with analgesic, anxiolytic and antiepileptic activity, has shown efficacy in the treatment of fibromyalgia. It has a multidimensional effect in the treatment of this complex condition, and is associated with rapid and clinically significant improvements in several outcome measures relating to core symptoms of the syndrome, including pain and sleep, in patients with long-standing fibromyalgia. Pregabalin treatment is also associated with improvements in the overall health status of these patients. The beneficial effects of pregabalin are durable in patients with an initial response to the drug. The most common adverse events associated with the drug are dizziness and somnolence, which are generally mild to moderate in intensity and are tolerated by many patients. Pregabalin is, therefore, a valuable option in the first-line treatment of patients with fibromyalgia.




Mary L. Forte, Treatments for Fibromyalgia in Adult Subgroups, Agency for Healthcare Research and Quality, AHRQ Publication No. 15-EHC006-EF

Objective. We conducted a systematic literature review of clinical trials to assess the comparative effectiveness of treatments for fibromyalgia in subgroups of highly affected or clinically complex adults. We focused on patient subgroups rather than overall treatment effects to complement a large systematic review being conducted on fibromyalgia treatments at McMaster University.
Data sources. We searched Medline®, Embase®, PsycINFO®, AMED, and the Cochrane Central Register of Controlled Trials (CENTRAL) plus reference lists of included studies and recent systematic reviews. Methods. Two investigators screened abstracts of identified references for eligibility (enrolled adults with fibromyalgia, examined treatment effects, had a control group, and assessed outcomes at least 3 months after treatment initiation). Full-text articles were reviewed to identify outcomes reporting for at least one adult subgroup: women, older or obese adults, individuals with coexisting mental health conditions, high severity or longer fibromyalgia duration, multiple medical comorbidities, or other chronic pain conditions. Primary outcomes included pain, symptom improvement, function, fatigue, sleep quality, participation, and health-related quality of life.We extracted data, assessed risk of bias of individual studies, and evaluated strength of evidence for each comparison and outcome.
Results. We identified 22 randomized controlled trials (RCTs), 8 pooled analyses of patient-level RCT data, and 4 observational studies that met inclusion criteria; 59 percent were drug trials. Adults with fibromyalgia and major depressive disorder (MDD) were studied most often; drug studies also reported outcomes by age, sex, race, and anxiety. Most drug trials examined duloxetine effects on pain and global improvement; trial duration was typically 3 months. Low-strength evidence for duloxetine suggests that subgroups of adults with fibromyalgia and MDD do not experience differential short-term treatment effects. Other subgroup evidence is largely insufficient. For nearly all comparisons, treatment-by-subgroup interactions were not significant. Most interaction results were reported in text; only two RCTs and five pooled RCT analyses displayed data on subgroup outcomes. Losses to followup were considerable; dropout reporting was not subgroup specific. Adverse effects were reported for the MDD subgroup in one duloxetine pooled analysis; these were similar to overall adverse effects. Studies were not powered to detect subgroup effects.
Conclusion. Despite the prevalent belief that fibromyalgia treatments may behave differently in subgroups, evidence to date is largely insufficient for fibromyalgia subgroup effects of interventions other than duloxetine in adults with concomitant MDD. Future studies should be designed to support subgroup analysis to improve clinical applicability.




Mease PJ, Russell IJ, Florian H, et al. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol 2008;35(3):502-514.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin for symptomatic relief of pain associated with fibromyalgia (FM) and for management of FM. METHODS: This multicenter, double-blind, placebo-controlled trial randomly assigned 748 patients with FM to receive placebo or pregabalin 300, 450, or 600 mg/day (dosed twice daily) for 13 weeks. The primary outcome variable for study objective 1, symptomatic relief of pain associated with FM, was comparison of endpoint mean pain scores between each pregabalin group and placebo. The outcome variable for study objective 2, management of FM, included endpoint mean pain scores, Patient Global Impression of Change (PGIC), and Fibromyalgia Impact Questionnaire (FIQ)-Total Score. Secondary outcomes included assessments of sleep, fatigue, and mood disturbance. RESULTS: Patients in all pregabalin groups showed statistically significant improvement in endpoint mean pain score and in PGIC response compared with placebo. Improvements in FIQ-Total Score for the pregabalin groups were numerically but not significantly greater than those for the placebo group. Compared with placebo, all pregabalin treatment groups showed statistically significant improvement in assessments of sleep and in patients' impressions of their global improvement. Dizziness and somnolence were the most frequently reported adverse events. CONCLUSION: Pregabalin at 300, 450, and 600 mg/day was efficacious and safe for treatment of pain associated with FM. Pregabalin monotherapy provides clinically meaningful benefit to patients with FM.




Ohta H, Oka H. An open-label long-term phase III extension trial to evaluate the safety and efficacy of pregabalin in Japanese patients with fibromyalgia. Mod Rheumatol. 2013;23(6):1108-1115.

OBJECTIVES: To assess the long-term safety and efficacy of pregabalin for the treatment of Japanese patients with fibromyalgia (FM). METHODS: This 53-week, open-label extension study was conducted at 20 study sites in Japan in patients with FM who had completed a preceding 16-week, placebo-controlled, double-blind trial. Patients received pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day. The primary endpoint was safety, and secondary endpoints included measures of pain, sleep, and physical functioning. RESULTS: 106 patients entered the trial and received at least one dose of the study drug. The most common treatment-related adverse events were somnolence, dizziness, increased weight, and constipation. There were no treatment-related serious or severe adverse events. There were five (4.7%) discontinuations due to adverse events, of which three (2.8%) were considered related to the study drug. Most adverse events resolved over time and could be managed without dose reduction or treatment discontinuation. Improvements in secondary efficacy endpoints of pain, sleep, and physical functioning emerged early in the study and were maintained for the duration of treatment. CONCLUSIONS: These data indicate that the long-term treatment of Japanese FM patients with pregabalin may be both safe and effective.

 



 


Pauer L, Atkinson G. Long-term maintenance of response across multiple fibromyalgia symptom domains in a randomized withdrawal study of pregabalin. Clin J Pain. 2012;e-pub ahead of print.

OBJECTIVE: To determine the incidence and duration of response of clinically meaningful improvements with pregabalin across several key symptoms of fibromyalgia (FM). METHODS: This was a post hoc analysis of data from a multicenter, double-blind, placebo-controlled, randomized, withdrawal study, originally designed to evaluate the efficacy of pregabalin monotherapy for durability of effect on FM pain based on pain and Patient Global Impression of Change (PGIC) criteria. Responder criteria for Fibromyalgia Impact Questionnaire total score (≥16-point change), Medical Outcomes Study Sleep Scale Sleep Disturbance subscale (≥15.8-point change), and the 36-item Short-Form Health Survey Vitality scale (≥10-point change) were used to evaluate the incidence and duration of improvements in function, sleep, and fatigue for pregabalin versus placebo among pain and PGIC responders. A composite responder index consisting of pain, PGIC, function, and sleep endpoints was used to explore multidimensional response. RESULTS: Approximately 80% of patients meeting pain and PGIC improvement criteria at randomization had clinically meaningful improvement in fatigue, sleep, or function. Higher proportions of patients in the pregabalin group maintained a clinically meaningful response, and pregabalin-treated patients had a significantly longer time to loss of therapeutic response compared with the placebo group. Composite responder Kaplan-Meier analysis, performed with patients demonstrating clinically meaningful improvements in pain, PGIC, function, and sleep at randomization showed a significantly longer median time to loss of therapeutic response for pregabalin-treated patients. DISCUSSION: The results from this post hoc analysis indicate that pregabalin provides long-term effects across multiple domains of FM




Pujol J, López-Solà M, Ortiz H, et al. Mapping brain response to pain in fibromyalgia patients using temporal analysis of fMRI. PLOS ONE. 4(4):e5224. doi:10.1371/journal.pone.0005224.

Abstract Background Nociceptive stimuli may evoke brain responses longer than the stimulus duration often partially detected by conventional neuroimaging. Fibromyalgia patients typically complain of severe pain from gentle stimuli. We aimed to characterize brain response to painful pressure in fibromyalgia patients by generating activation maps adjusted for the duration of brain responses. Methodology/Principal Findings Twenty-seven women (mean age: 47.8 years) were assessed with fMRI. The sample included nine fibromyalgia patients and nine healthy subjects who received 4 kg/cm2 of pressure on the thumb. Nine additional control subjects received 6.8 kg/cm2 to match the patients for the severity of perceived pain. Independent Component Analysis characterized the temporal dynamics of the actual brain response to pressure. Statistical parametric maps were estimated using the obtained time courses. Brain response to pressure (18 seconds) consistently exceeded the stimulus application (9 seconds) in somatosensory regions in all groups. fMRI maps following such temporal dynamics showed a complete pain network response (sensory-motor cortices, operculo-insula, cingulate cortex, and basal ganglia) to 4 kg/cm2 of pressure in fibromyalgia patients. In healthy subjects, response to this low intensity pressure involved mainly somatosensory cortices. When matched for perceived pain (6.8 kg/cm2), control subjects showed also comprehensive activation of pain-related regions, but fibromyalgia patients showed significantly larger activation in the anterior insula-basal ganglia complex and the cingulate cortex. Conclusions/Significance The results suggest that data-driven fMRI assessments may complement conventional neuroimaging for characterizing pain responses and that enhancement of brain activation in fibromyalgia patients may be particularly relevant in emotion-related regions.




Roth T, Lankford DA. Effect of pregabalin on sleep in patients with fibromyalgia and sleep maintenance disturbance: a randomized, placebo-controlled, 2-way crossover polysomnography study. Arthritis Care Res. 2012;64(4):597-606.

OBJECTIVE: To assess the effect of pregabalin on polysomnographic (PSG) measures of sleep and patient-rated sleep, tiredness, and pain in fibromyalgia patients. METHODS: We performed a randomized, double-blind, placebo-controlled, 2-period crossover PSG study. Patients ages ≥18 years with fibromyalgia satisfied subjective and objective sleep disturbance criteria prior to randomization. Eligible patients were randomized (1:1) to pregabalin (300-450 mg/day) or placebo for crossover period 1, and vice versa for period 2. Each crossover period comprised a dose-adjustment and dose-maintenance phase, with a 2-week taper/washout between periods. In-laboratory PSGs were recorded during 2 consecutive nights at screening and at the end of each crossover period. The primary end point was the difference in sleep maintenance defined by PSG-recorded wake after sleep onset (WASO; minutes) between 4 weeks of treatment with pregabalin and with placebo. Other PSG measures; patient-rated sleep, tiredness, and pain; and tolerability were assessed. RESULTS: Of 119 patients randomized (103 women [86.6%], mean age 48.4 years), 102 (85.7%) completed both periods. Patients treated with pregabalin showed a reduction in PSG-determined WASO versus treatment with placebo (week 4 difference: -19.2 minutes [95% confidence interval (95% CI) -26.7, -11.6]; P < 0.0001). Pain score improved (decreased) with pregabalin versus placebo treatment at all 4 weeks (week 4 difference: -0.52 [95% CI -0.90, -0.14]; P = 0.0084). Modest (ρ = <0.3) but significant correlations were found between PSG sleep assessments and ratings of pain and sleep quality. Frequently reported all-causality adverse events (pregabalin versus placebo) were: dizziness (30.4% versus 9.9%), somnolence (20.5% versus 4.5%), and headache (8.9% versus 8.1%). CONCLUSION: Patients with fibromyalgia treated with pregabalin had statistically significant and meaningful improvements in sleep, as assessed by PSG. Patients with fibromyalgia also reported decreased daily pain. Pregabalin was well tolerated.




Russell IJ, Vaeroy H. Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthr Rheum. 1992;35(5):550-556.

OBJECTIVE: To compare the levels of biogenic amines in the cerebrospinal fluid (CSF) of primary fibromyalgia syndrome (PFS) patients with those in the CSF of controls. METHODS: Metabolites of serotonin, norepinephrine, and dopamine were identified in CSF, using high performance liquid chromatography with coulometric detection. RESULTS: CSF levels of metabolites from all 3 neurotransmitters were lower in PFS patients than in controls. CONCLUSION: A low rate of turnover of several neurotransmitters supports the proposed hypothesis of a metabolic defect in PFS and suggests that the defect occurs at a neuroregulatory level.




Russell IJ, Orr MD, Littman B, et al. Elevated cerebrospinal fluid levels of substance P in patients with fibromyalgia syndrome. Arthr Rheum. 1994;37(11):1593-1601.

OBJECTIVE: To measure, and seek clinical correlates with, levels of substance P (SP) in the cerebrospinal fluid (CSF) of fibromyalgia syndrome (FMS) patients. METHODS: CSF from 32 FMS patients and 30 normal control subjects was tested for SP by radioimmunoassay. Clinical measures included tender point examination and standardized questionnaires. RESULTS: CSF SP levels were 3-fold higher in FMS patients than in normal controls (P < 0.001), but they correlated only weakly with tenderness found on examination. CONCLUSION: SP is significantly elevated in FMS CSF, but other abnormalities must exist in FMS to more fully explain the symptoms.




Sarchielli P, Mancini ML, Floridi A, et al. Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome. J Pain. 2007;8(9):737-745.

All data obtained in experimental animal pain models support the role of nerve growth factor (NGF) as a putative candidate intervening in the pathogenesis of chronic pain, including chronic daily headache (CDH). Few studies have been carried out to establish its role in maintaining pain states in humans. The present study was aimed at investigating cerebrospinal fluid (CSF) levels of NGF and brain-derived neurotrophic factor (BDNF), both measured by sensitive immunoassay, in 20 chronic migraine (CM) patients and 20 patients affected by primary fibromyalgia syndrome (PFMS), compared with those of 20 age-matched control subjects. Significantly higher levels of both neurotrophins and glutamate were found. A significantly positive correlation emerged between CSF values of BDNF and those of NGF (r = .61, P < .001; r = .53, P < .01) and glutamate (r = .44, P < .02; r = .51, P < .01) in CM and PFMS patients, respectively. These findings suggest the possibility of a NGF-mediated up-regulation of BDNF involved in the pathophysiological events underlying long-term neuroplastic changes in persistent chronic painful conditions, such as CM and fibromyalgia. NGF might indirectly exert its effect through enhancing glutamatergic transmission via BDNF. The above mechanisms could account for sustained central sensitization in both chronic pain states.




Toth Cory, Pregabalin: latest safety evidence and clinical implications for the management of neuropathic pain, Ther Adv Drug Saf 2014, Vol. 5(1) 38–56 DOI: 10.1177/2042098613505614

Used mainly for the management of neuropathic pain, pregabalin is a gabapentinoid or anticonvulsant that was initially developed as an antiepileptic agent. After more than a decade of experience with pregabalin, experience and studies have shown that the adverse effect profile of pregabalin is well tolerated for the management of neuropathic pain and other conditions. Its use is associated with benign central nervous system and systemic adverse effects, and there are very limited metabolic, idiosyncratic or known teratogenic adverse effects. Along with its efficacy in particular neuropathic pain conditions, pregabalin’s safety led it to be one of the first pharmacotherapies considered for the management of neuropathic pain. This review discusses the use of pregabalin as well as its potential adverse effects, including the most commonly noted features of sedation, dizziness, peripheral edema and dry mouth. Although other adverse effects may occur, these appear to be uncommon. The review also discusses the clinical implications of pregabalin’s use for the clinician.




Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33(2):160-172.

To develop criteria for the classification of fibromyalgia, we studied 558 consecutive patients: 293 patients with fibromyalgia and 265 control patients. Interviews and examinations were performed by trained, blinded assessors. Control patients for the group with primary fibromyalgia were matched for age and sex, and limited to patients with disorders that could be confused with primary fibromyalgia. Control patients for the group with secondary-concomitant fibromyalgia were matched for age, sex, and concomitant rheumatic disorders. Widespread pain (axial plus upper and lower segment plus leftand right-sided pain) was found in 97.6% of all patients with fibromyalgia and in 69.1% of all control patients. The combination of widespread pain and mild or greater tenderness in greater than or equal to 11 of 18 tender point sites yielded a sensitivity of 88.4% and a specificity of 81.1%. Primary fibromyalgia patients and secondary-concomitant fibromyalgia patients did not differ statistically in any major study variable, and the criteria performed equally well in patients with and those without concomitant rheumatic conditions. The newly proposed criteria for the classification of fibromyalgia are 1) widespread pain in combination with 2) tenderness at 11 or more of the 18 specific tender point sites. No exclusions are made for the presence of concomitant radiographic or laboratory abnormalities. At the diagnostic or classification level, the distinction between primary fibromyalgia and secondary-concomitant fibromyalgia (as defined in the text) is abandoned.




Wolfe F, Ross K. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995;38(1):19-28.

OBJECTIVE: To determine the prevalence and characteristics of fibromyalgia in the general population. METHODS: A random sample of 3,006 persons in Wichita, KS, were characterized according to the presence of no pain, non-widespread pain, and widespread pain. A subsample of 391 persons, including 193 with widespread pain, were examined and interviewed in detail. RESULTS: The prevalence of fibromyalgia was 2.0% (95% confidence interval [95% CI] 1.4, 2.7) for both sexes, 3.4% (95% CI 2.3, 4.6) for women, and 0.5% (95% CI 0.0, 1.0) for men. The prevalence of the syndrome increased with age, with highest values attained between 60 and 79 years (> 7.0% in women). Demographic, psychological, dolorimetry, and symptom factors were associated with fibromyalgia. CONCLUSION: Fibromyalgia is common in the population, and occurs often in older persons. Characteristic features of fibromyalgia--pain threshold and symptoms--are similar in community and clinic populations, but overall severity, pain, and functional disability are more severe in the clinic population.

 

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