sodium-oxybate and Fibromyalgia

The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most recommendations were 'expert opinion'.. A multidisciplinary group from 12 countries assessed evidence with a focus on systematic reviews and meta-analyses concerned with pharmacological/non-pharmacological management for fibromyalgia. A review, in May 2015, identified eligible publications and key outcomes assessed were pain, fatigue, sleep and daily functioning. The Grading of Recommendations Assessment, Development and Evaluation system was used for making recommendations.. 2979 titles were identified: from these 275 full papers were selected for review and 107 reviews (and/or meta-analyses) evaluated as eligible. Based on meta-analyses, the only 'strong for' therapy-based recommendation in the guidelines was exercise. Based on expert opinion, a graduated approach, the following four main stages are suggested underpinned by shared decision-making with patients. Initial management should involve patient education and focus on non-pharmacological therapies. In case of non-response, further therapies (all of which were evaluated as 'weak for' based on meta-analyses) should be tailored to the specific needs of the individual and may involve psychological therapies (for mood disorders and unhelpful coping strategies), pharmacotherapy (for severe pain or sleep disturbance) and/or a multimodal rehabilitation programme (for severe disability).. These recommendations are underpinned by high-quality reviews and meta-analyses. The size of effect for most treatments is relatively modest. We propose research priorities clarifying who will benefit from specific interventions, their effect in combination and organisation of healthcare systems to optimise outcome.

Topics: Activities of Daily Living; Acupuncture Therapy; Amitriptyline; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Antidepressive Agents, Tricyclic; Biofeedback, Psychology; Capsaicin; Cognitive Behavioral Therapy; Europe; Evidence-Based Medicine; Exercise Therapy; Fatigue; Fibromyalgia; Human Growth Hormone; Humans; Hydrotherapy; Hypnosis; Manipulation, Chiropractic; Massage; Mind-Body Therapies; Mindfulness; Monoamine Oxidase Inhibitors; Pain; Practice Guidelines as Topic; S-Adenosylmethionine; Selective Serotonin Reuptake Inhibitors; Sensory System Agents; Serotonin and Noradrenaline Reuptake Inhibitors; Sleep; Societies, Medical; Sodium Oxybate; Treatment Outcome

The US Federal Drug Administration (FDA) approved 3 medications for treating fibromyalgia syndrome (FMS). There have been no additional FDA approvals since January 2009 and the efficacy of the FDA-approved medications for FMS has been questioned. Areas covered: The "search for studies" tool using clinicaltrials.gov and PubMed were employed. The term, "fibromyalgia" was used for clinicaltrials.gov. The terms employed for PubMed were "Name-of-Drug Fibromyalgia", "Fibromyalgia Treatment" or "Fibromyalgia Drug Treatment." Clinical trials were reviewed if they were prospective and blinded, and if they employed a comparator, either placebo or another pharmaceutical. Expert commentary: Progress toward standardizing the outcome measures for FMS clinical trials have been made but challenges remain. Several pharmaceutical candidates for FMS have been tested since 2009. The results of these studies with potential novel targets for drug development for FMS were reviewed including the results of trials with sodium oxybate, quetiapine, esreboxetine, nabilone, memantine, naltrexone, and melatonin.

Topics: Dronabinol; Drug Discovery; Fibromyalgia; Humans; Prospective Studies; Sodium Oxybate

Fibromyalgia is a syndrome characterized by the presence of chronic widespread pain, representing sensitization of the central nervous system. The pthophysiology of fibromyalgia is a complex and remains in evolution, encompassing diverse issues such as disturbed patterns of sleep, alter processing and decreased conditioned pain modulation at the spinal level, as well as increased connectivity between various pain - processing areas of the brain. This evolution is continuously uncovering potential novel therapeutic targets. Treatment of fibromyalgia is a multi - faceted endeavor, inevitably combining pharmacological as well as non - pharmacological approaches. 2δ ligands and selective nor-epinephrine - serotonin reuptake inhibitors are the current mainstays of pharmacological treatment. Novel re-uptake inhibitors targeting both nor -epinephrine and dopamine are potential additions to this armamentarium as are substance P antagonists, Opiod antagonism is another intriguing possibility. Canabinoid agonists hold promise in the treatment of fibromyalgia although current evidence is incomplete. Sodium Oxybate is a unique sleep - promoting medication while drugs those promot arousals such as modafilnil are also under investigation. In the current review, current and emerging therapeutic options for the syndrome of fibromyalgia are covered.

Topics: Central Nervous System Agents; Chronic Pain; Fibromyalgia; Humans; Neurotransmitter Agents; Sleep; Sodium Oxybate; Syndrome

Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid that is synthesized within the CNS, mostly from its parent compound gamma amino butyric acid (GABA). GHB acts as a neuromodulator/neurotransmitter to affect neuronal activity of other neurotransmitters and so, stimulate the release of growth hormone. Its sodium salt (sodium oxybate: SXB) was approved by the Food and Drug Administration (FDA) for the treatment of narcolepsy. SXB has shown to improve disrupted sleep and increase NR3 (slow-wave restorative) sleep in patients with narcolepsy. It is rapidly absorbed and has a plasma half-life of 30 - 60 min, necessitating twice-nightly dosing. Most of the observed effects of SXB result from binding to GABA-B receptors.. Several randomized, controlled trials demonstrated significantly improved fibromyalgia (FM) symptoms with SXB. As seen in narcolepsy trials, SXB improved sleep of FM patients, increased slow-wave sleep duration as well as delta power, and reduced frequent night-time awakenings. Furthermore, FM pain and fatigue was consistently reduced with nightly SXB over time. Commonly reported adverse events included headache, nausea, dizziness and somnolence. Despite its proven efficacy, SXB did not receive FDA approval for the management of FM in 2010, mostly because of concerns about abuse.. Insomnia, fatigue and pain are important clinical FM symptoms that showed moderate improvements with SXB in several large, well-designed clinical trials. Because of the limited efficacy of currently available FM drugs additional treatment options are needed. In particular, drugs like SXB - which belong to a different drug class than other Food and Drug Administration (FDA)-approved FM medications such as pregabalin, duloxetine and milnacipran - would provide a much-needed addition to presently available treatment options. However, the FDA has set the bar high for future SXB re-submissions, with requirements of superior efficacy and improved risk mitigation strategies. At this time, no future FDA submission of SXB for the fibromyalgia indication is planned.

Topics: Adjuvants, Anesthesia; Animals; Drug Approval; Fibromyalgia; Humans; Pain; Protein Binding; Receptors, GABA-B; Sleep Wake Disorders; Sodium Oxybate; United States; United States Food and Drug Administration

The etiology of fibromyalgia syndrome is not yet fully understood. Current hypotheses suggest a potential role of gamma-hydroxybutyrate (GHB) in influencing endocrinological abnormalities in patients with fibromyalgia.. The aim of the study was to investigate whether low dose GHB as a growth-hormone releasing substance reduces pain intensity and improves depressive mood, physical impairment and sleep quality in outpatients with fibromyalgia. Additionally, adverse events were recorded.. The pilot study was conducted in the outpatient clinic for pain at the clinic for anesthesiology and surgical intensive care of the Charité Universitätsmedizin Berlin. In the study 25 female patients with fibromyalgia according to the criteria of the American College of Rheumatology were randomized into 2 groups. Over 15 weeks patients of the intervention group received 25 mg/kg body weight oral GHB before going to bed and were compared with a placebo control group. In addition, all patients participated in operant behavioral pain treatment in a group setting. Dependent variables were pain intensity, depressive mood, physical impairment and quality of sleep.. There were no group differences in the course of pain intensity (p = 0.61), depressive mood (p = 0.16), physical impairment (p = 0.25) and quality of sleep (p = 0.44); however, all symptoms improved across the groups from pretherapy to posttherapy. Low dose GHB did not increase growth hormone blood concentrations. The number of adverse events that were reported more than two times was similar in both groups.. Administration of low dose GHB did not yield clinical improvements in female outpatients with fibromyalgia. General improvement in the course of treatment may have resulted from operant behavioral pain therapy. Future studies on GHB should control hypothetical risk factors for identification of non-responders.

Topics: Administration, Oral; Behavior Therapy; Combined Modality Therapy; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fibromyalgia; Hospitals, University; Humans; Male; Middle Aged; Outpatient Clinics, Hospital; Pain Measurement; Pilot Projects; Sodium Oxybate

The long-term safety and therapeutic response of sodium oxybate (SXB) in fibromyalgia syndrome (FM) patients were assessed for a combined period of up to 1 year in a prospective, multicenter, open-label, extension study in patients completing 1 of 2 phase 3 randomized, double-blind, controlled, 14-week trials that examined the efficacy and safety of SXB 4.5 g, SXB 6 g, and placebo for treatment of FM.. This extension study comprised an additional 38 weeks of treatment and was carried out at 130 clinical sites in 7 countries. Initial entry criteria for the previous 2 double-blind clinical trials required that patients aged ≥ 18 years met the American College of Rheumatology 1990 criteria for FM, had a body mass index (BMI) < 40 kg/m2, and had a score ≥ 50 on a 100-mm pain visual analog scale (VAS) at baseline. All patients began treatment in the extension study with SXB 4.5 g/night (administered in 2 equally divided doses) for at least 1 week, followed by possible serial 1.5 g/night dose increases to 9 g/night (maximum) or reductions to 4.5 g/night (minimum).. Of the 560 FM patients enrolled in this extension study, 319 (57.0%) completed the study. The main reason for early discontinuation was adverse events (AEs; 23.0% of patients). Patients were primarily middle-aged (mean 46.9 ± 10.8 years), female (91.1%), white (91.4%), with a mean duration of FM symptoms of 9.9 ± 8.7 years. Serious AEs were experienced by 3.6% of patients. The most frequently reported AEs (incidence ≥ 5% at any dose or overall) were nausea, headache, dizziness, nasopharyngitis, vomiting, sinusitis, diarrhea, anxiety, insomnia, influenza, somnolence, upper respiratory tract infection, muscle spasms, urinary tract infection, and gastroenteritis viral. Maintenance of SXB therapeutic response was demonstrated with continued improvement from controlled-study baseline in pain VAS, Fibromyalgia Impact Questionnaire (FIQ) total scores, and other measures. Responder analyses showed that 68.8% of patients achieved ≥ 30% reduction in pain VAS and 69.7% achieved ≥ 30% reduction in FIQ total score at study endpoint.. The long-term safety profile of SXB in FM patients was similar to that in the previously reported controlled clinical trials. Improvement in pain and other FM clinical domains was maintained during long-term use.. ClinicalTrials.gov NCT00423605.

Topics: Adult; Aged; Central Nervous System Depressants; Double-Blind Method; Female; Fibromyalgia; Humans; Male; Middle Aged; Pain Measurement; Sodium Oxybate; Time

Fibromyalgia is characterised by chronic musculoskeletal pain and multiple symptoms including fatigue, multidimensional function impairment, sleep disturbance and tenderness. Along with pain and fatigue, non-restorative sleep is a core symptom of fibromyalgia. Sodium oxybate (SXB) is thought to reduce non-restorative sleep abnormalities. This study evaluated effects of SXB on fibromyalgia-related pain and other symptoms.. 573 patients with fibromyalgia according to 1990 American College of Rheumatology criteria were enrolled at 108 centres in eight countries. Subjects were randomly assigned to placebo, SXB 4.5 g/night or SXB 6 g/night. The primary efficacy endpoint was the proportion of subjects with ≥30% reduction in pain visual analogue scale from baseline to treatment end. Other efficacy assessments included function, sleep quality, effect of sleep on function, fatigue, tenderness, health-related quality of life and subject's impression of change in overall wellbeing.. Significant improvements in pain, sleep and other symptoms associated with fibromyalgia were seen in SXB treated subjects compared with placebo. The proportion of subjects with ≥30% pain reduction was 42.0% for SXB4.5 g/night (p=0.002) and 51.4% for SXB6 g/night (p<0.001) versus 26.8% for placebo. Quality of sleep (Jenkins sleep scale) improved by 20% for SXB4.5 g/night (p≤0.001) and 25% for SXB6 g/night (p≤0.001) versus 0.5% for placebo. Adverse events with an incidence ≥5% and twice placebo were nausea, dizziness, vomiting, insomnia, anxiety, somnolence, fatigue, muscle spasms and peripheral oedema.. These results, combined with findings from previous phase 2 and 3 studies, provide supportive evidence that SXB therapy affords important benefits across multiple symptoms in subjects with fibromyalgia.

Topics: Adjuvants, Anesthesia; Adult; Female; Fibromyalgia; Follow-Up Studies; Health Status; Humans; Male; Middle Aged; Musculoskeletal Pain; Patient Satisfaction; Quality of Life; Sleep; Sleep Wake Disorders; Sodium Oxybate

This 14-week, phase 3, double-blind, randomized, controlled trial evaluated sodium oxybate (SXB) 4.5 and 6g per night versus placebo in patients with fibromyalgia (FM). SXB is the sodium salt of γ-hydroxybutyrate (GHB). GHB is an endogenous compound, synthesized from γ-aminobutyric acid (GABA) and found broadly in the central nervous system and body. Among 548 randomized patients, a ≥30% reduction in pain was experienced by 54.2% and 58.5% of patients treated with SXB 4.5 and 6g, respectively, versus 35.2% for placebo with a 100-mm Visual Analog Scale (VAS) (P<0.001 for both comparisons). Relative to placebo, both SXB doses significantly reduced fatigue (with a 100-mm VAS; P<0.001) and sleep disturbance (with the Jenkins Sleep Scale; P<0.001), and resulted in significant improvements in function as measured by the FM Impact Questionnaire (P=0.003 and P=0.001 for 4.5 and 6 g per night, respectively). On the Short-Form 36 Health Survey, SXB-related improvement was significant on the Physical, but not the Mental, Component Scale. The proportion of patients who reported a global improvement of "much" or "very much" better on the Patient Global Impression of Change was significantly greater in both SXB groups versus placebo (P<0.001). Headache, nausea, dizziness, vomiting, diarrhea, anxiety, and sinusitis were the most commonly reported adverse events, with an incidence at least twice that of placebo. These results expand the evidence from previous clinical trials suggesting that SXB is effective and safe in FM.

Topics: Adjuvants, Anesthesia; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Fatigue; Female; Fibromyalgia; Humans; Male; Middle Aged; Pain; Pain Measurement; Quality of Life; Sleep Wake Disorders; Sodium Oxybate; Treatment Outcome

To determine the effects of sodium oxybate (SXB) on sleep physiology and sleep/wake-related symptoms in patients with fibromyalgia syndrome (FM).. Of 304 patients with FM (American College of Rheumatology tender point criteria) in the screened study population, 209 underwent polysomnography, 195 were randomized, and 151 completed this 8-week, double-blind, placebo-controlled study of SXB 4.5 g and 6 g/night. We evaluated changes in objective sleep measures and subjective symptoms, including daytime sleepiness [Epworth Sleepiness Scale (ESS)], fatigue visual analog scale (FVAS), sleep [Jenkins Scale for Sleep (JSS)], and daytime functioning [Functional Outcome of Sleep Questionnaire (FOSQ), SF-36 Vitality domain, and Fibromyalgia Impact Questionnaire (FIQ) general and morning tiredness].. Pretreatment screening revealed an elevated incidence of maximum alpha EEG-intrusion > 24 min/hour of sleep (66%), periodic limb movements of sleep (20.1% ≥ 5/hour), and moderate to severe obstructive sleep apnea disorder (15.3% apnea-hypopnea index ≥ 15/hour). Compared with placebo, both doses of SXB achieved statistically significant improvements in ESS, morning FVAS, JSS, FOSQ, SF-36 Vitality, and FIQ general and morning tiredness; both doses also demonstrated decreased rapid eye movement (REM) sleep (all p ≤ 0.040). SXB 6 g/night improved afternoon, evening and overall FVAS, reduced wakefulness after sleep onset, and increased Stage 2, slow-wave, and total non-REM sleep (all p ≤ 0.032) versus placebo. Moderate correlations (≥ 0.40) were noted between changes in subjective sleep and pain measures. Adverse events occurring significantly more frequently with SXB than placebo were nausea, pain in extremity, nervous system disorders, dizziness, restlessness, and renal/urinary disorders (including urinary incontinence).. This large cohort of patients with FM demonstrated that SXB treatment improved EEG sleep physiology and sleep-related FM symptoms.

Topics: Adjuvants, Anesthesia; Adult; Double-Blind Method; Female; Fibromyalgia; Humans; Male; Middle Aged; Placebos; Polysomnography; Sleep; Sleep Wake Disorders; Sodium Oxybate; Surveys and Questionnaires; Treatment Outcome

To evaluate the safety and efficacy of sodium oxybate for management of the symptoms of fibromyalgia syndrome (FMS).. Patients with FMS (according to the American College of Rheumatology 1990 criteria) were randomized, after discontinuing their prestudy medications for FMS, to receive 4.5 gm or 6 gm of sodium oxybate or matching placebo once per night for 8 weeks. The primary outcome variable (POV) was a composite score for changes from baseline in 3 coprimary self-report measures: patient's pain rating (in daily electronic diaries) on a visual analog scale (PVAS), the Fibromyalgia Impact Questionnaire (FIQ) score, and the Patient Global Impression of Change (PGI-C). A beneficial response rate for the POV composite score was defined as >or=20% improvement in the PVAS and FIQ scores plus a rating of "much better" or "very much better" on the PGI-C. Secondary measures included subjective sleep outcomes (on the Jenkins Scale for Sleep) and quality-of-life measures. The analyses were based on an intent-to-treat (ITT) population.. The ITT population included 188 patients with FMS, 78% of whom completed the trial. Significant benefit was observed with both dosages of sodium oxybate, according to changes in the POV and subjective sleep quality. Improvements in the PVAS score were significantly correlated with sleep outcomes. Sodium oxybate was well tolerated overall; dose-related nausea (

Topics: Adjuvants, Anesthesia; Adult; Anxiety; Double-Blind Method; Female; Fibromyalgia; Humans; Male; Middle Aged; Pain; Patient Compliance; Placebos; Quality of Life; Sleep Initiation and Maintenance Disorders; Sodium Oxybate; Treatment Outcome

Fibromyalgia (FM) is associated with the sleep phenomenon of alpha intrusion, and with low growth hormone secretion. Sodium oxybate has been shown to increase both slow-wave sleep and growth hormone levels. This double blind, randomized, placebo controlled crossover trial was conducted to evaluate the effects of sodium oxybate on the subjective symptoms of pain, fatigue, and sleep quality and the objective polysomnographic (PSG) sleep variables of alpha intrusion, slow-wave (stage 3/4) sleep, and sleep efficiency in patients with FM.. Patients received either 6.0 g/day sodium oxybate or placebo for 1 month, with an intervening 2 week washout period. Efficacy measures included PSG evaluations, tender point index (TPI), and subjective measurements from daily diary entries. Safety measures included clinical laboratory values, vital signs, and adverse events.. Twenty-four female patients were included in the study; 18 completed the trial. TPI was decreased from baseline by 8.5, compared with an increase of 0.4 for placebo (p = 0.0079). Six of the 7 pain/fatigue scores (overall pain, pain at rest, pain during movement, end of day fatigue, overall fatigue, and morning fatigue) were relieved by 29% to 33% with sodium oxybate, compared with 6% to 10% relief with placebo (p < 0.005). Alpha intrusion, sleep latency, and rapid-eye-movement sleep were significantly decreased, while slow-wave (stage 3/4) sleep was significantly increased, compared with placebo (p < 0.005). Two of the 5 subjective sleep related variables were significantly different from placebo: morning alertness (improved by 18% with sodium oxybate, compared with 2% for placebo; p = 0.0033) and quality of sleep (improved by 33% and 10%, respectively; p = 0.0003).. Sodium oxybate effectively reduced the symptoms of pain and fatigue in patients with FM, and dramatically reduced the sleep abnormalities (alpha intrusion and decreased slow-wave sleep) associated with the nonrestorative sleep characteristic of this disorder.

Topics: Adjuvants, Anesthesia; Adult; Aged; Alpha Rhythm; Cross-Over Studies; Female; Fibromyalgia; Humans; Middle Aged; Sleep Wake Disorders; Sleep, REM; Sodium Oxybate; Treatment Outcome

To evaluate the effects of using a gamma-hydroxybutyrate (GHB) administered in divided doses at night in 11 patients previously diagnosed with fibromyalgia (FM).. Subjects completed daily diaries assessing their pain and fatigue levels and slept in the sleep laboratory before and one month after initiating GHB treatment. Polysomnographic recordings were evaluated for sleep stages, sleep efficiency and the presence of the alpha anomaly in non-REM sleep.. There was a significant improvement in both fatigue and pain, with an increase in slow wave sleep and a decrease in the severity of the alpha anomaly.. Further controlled studies are needed to characterize the clinical improvement and the polysomnographic changes we observed.

Topics: Adult; Fatigue; Female; Fibromyalgia; Humans; Male; Middle Aged; Pain; Pilot Projects; Polysomnography; Sleep Wake Disorders; Sodium Oxybate

Alpha-delta sleep is the abnormal intrusion of alpha activity (8- to 13-Hz oscillations) into the delta activity (1- to 4-Hz oscillations) that defines slow-wave sleep. Alpha-delta sleep is especially prevalent in fibromyalgia patients, and there is evidence suggesting that the irregularities in the sleep of these patients may cause the muscle and tissue pain that characterizes the disorder. We constructed a biophysically realistic mathematical model of alpha-delta sleep. Imaging studies in fibromyalgia patients suggesting altered levels of activity in the thalamus motivated a thalamic model as the source of alpha activity. Since sodium oxybate helps to alleviate the symptoms of fibromyalgia and reduces the amount of alpha-delta sleep in fibromyalgia patients, we examined how changes in the molecular targets of sodium oxybate affected alpha-delta activity in our circuit. Our model shows how alterations in GABAB currents and two thalamic currents, Ih (a hyperpolarization-activated current) and a potassium leak current, transform a circuit that normally produces delta oscillations into one that produces alpha-delta activity. Our findings suggest that drugs that reduce Ih conductances and/or increase potassium conductances, without necessarily increasing GABAB conductances, might be sufficient to restore delta sleep. Furthermore, they suggest that delta sleep might be restored by drugs that preferentially target these currents in the thalamus; such drugs might have fewer side effects than drugs that act systemically.

Topics: Action Potentials; Alpha Rhythm; Delta Rhythm; Female; Fibromyalgia; GABAergic Neurons; gamma-Aminobutyric Acid; Humans; Models, Neurological; Potassium; Sleep Stages; Sodium Oxybate; Thalamus

Topics: Adjuvants, Anesthesia; Drug Approval; European Union; Fibromyalgia; Humans; Sodium Oxybate

Topics: Adjuvants, Anesthesia; Dose-Response Relationship, Drug; Fibromyalgia; Humans; Patient Compliance; Sodium Oxybate; Treatment Outcome

Topics: Adjuvants, Anesthesia; Alpha Rhythm; Fatigue; Fibromyalgia; Humans; Pain; Sodium Oxybate