sodium-oxybate and Pain

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

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

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 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

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

Chronic pain and sleep disorder can put the patient in a vicious circle (bidirectional relation between those two morbid entities). Clinical management must be global. The physiopathology includes chronic sleep deficit, mainly in deep sleep (the "restoring" sleep) generated principally by the prefrontal regions. These areas are also implicated in the modulation of pain. To break this "loops", we advocate an approach based on three main components: hygiene principles, cognitive and behavioral therapy, medications with analgesic and hypnotic proprieties.

Topics: Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Anticonvulsants; Behavior Therapy; Brain; Chronic Disease; Cognitive Behavioral Therapy; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Hypnotics and Sedatives; Life Style; Melatonin; Pain; Pain Management; Placebos; Sleep Initiation and Maintenance Disorders; Sodium Oxybate; Treatment Outcome

Topics: Adjuvants, Anesthesia; Adult; Fractures, Bone; Humans; Male; Pain; Pelvic Bones; Sodium Oxybate; Substance Withdrawal Syndrome

It has been reported that ethanol enhances the hypnotic effect of gamma-hydroxybutyrate (GHB). In order to clarify the nature of this interaction we studied the pharmacokinetics and pharmacodynamics of combinations of GHB and ethanol in rats. Intraperitoneal injections of the GHB precursor gamma-butyrolactone (300 mg/kg) together with ethanol (3000 mg/kg) (n = 4) resulted in a longer "sleeping time" than the sum of the individual times (n = 8). Pharmacokinetic analysis of GHB concentrations with a two-compartment model with Michaelis-Menten (M-M) elimination in rats receiving a bolus of GHB (400 mg/kg, i.v.) in addition to steady-state ethanol concentrations (300-3000 microg/ml) (n = 12) or saline (n = 15) showed no marked differences in the area under the curve. The nature of the pharmacodynamic interaction was studied using isobolographs and an interaction model for the loss of the startle and righting reflex and a reaction to a painful tail clamp in rats receiving combinations of steady state concentrations of ethanol (1000-3000 microg/ml) and GHB (200-1400 microg/ml). For the righting reflex, synergy was observed at high ethanol concentrations (>2000 microg/ml) and additivity at lower concentrations. For the startle reflex, it was antagonistic at ethanol concentrations below 1000 microg/ml, and additivity was seen at higher concentrations. For the tail clamp reaction, a slight but significant antagonism was found at all combined concentrations. It is concluded that ethanol prolongs the sleeping time induced by GHB in the rat, which may not be due to a pharmacokinetic interaction. Pharmacodynamic interactions between GHB and ethanol in the rat occur, and the nature varies with the reflex studied and the concentration of ethanol used.

Topics: 4-Butyrolactone; Adjuvants, Anesthesia; Animals; Behavior, Animal; Central Nervous System Depressants; Dose-Response Relationship, Drug; Drug Synergism; Ethanol; Illicit Drugs; Injections, Intraperitoneal; Injections, Intravenous; Male; Pain; Postural Balance; Rats; Rats, Wistar; Reflex, Startle; Sleep; Sodium Oxybate

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

Topics: Animals; Arthritis, Experimental; Pain; Pain Threshold; Peripheral Nervous System Diseases; Rats; Sodium Oxybate

The anxiety neurosis decreased the catecholamine concentration in the rat striatum, hypothalamus, adrenal cortex, heart and small intestine. The decrease in noradrenaline concentration during the stress was followed by activation of the synthesis and suppression of the transmitter binding in the heart as well as enhancement of the adreno- and cholino-reactivity in the small intestine. Absence of noradrenaline content changes during stress in the seminal duct was followed by no changes of adreno-reactivity in this organ. Preliminary administration of 75 mg/kg of GABA prevented the above changes during the stress. This defensive action of the GABA seems to be based on limiting the activation of sympathetic-adrenal system and decrease of the respective transmitter release.

Topics: Adrenal Glands; Animals; Catecholamines; Corpus Striatum; Humans; Hydroxybutyrates; Hypothalamus; Intestine, Small; Male; Myocardium; Pain; Rats; Sodium Oxybate; Stress, Psychological; Vas Deferens

Marked disorders of energy metabolism in the heart muscle simultaneously with the development of ulcerous lesions of the stomach were revealed in animals which had suffered an emotional-pain stress (EPS). These disorders are displayed in the fact that two hours after EPS, the glycogen reserve in the animal's myocardium diminishes, resynthesis of glycogen and oxidation of the main substrates of the tricarboxylic acid cycle are inhibited, and malate dehydrogenase and possibly other dehydrogenase systems of the mitochondria are partly inactivated. Such decrease in the activity of the metabolic tracts is attended by depression of the force and rate of cardiac contractions revealed on inducing a high rate of contractions. The preliminary administration of sodium gammaoxybutyrate to a considerable extent prevents all the changes in the animal's myocardium occurring due to the effect of EPS.

Topics: Animals; Citric Acid Cycle; Energy Metabolism; Enzyme Activation; Female; gamma-Aminobutyric Acid; Glycogen; Humans; Hydroxybutyrates; Myocardium; Oxidation-Reduction; Pain; Rats; Sodium Oxybate; Stress, Psychological