GHB gamma-hydroxy butyrate & Fibromyalgia
The Effects of Sodium Oxybate on Clinical Symptoms and Sleep Patterns in Patients with Fibromyalgia
Scharf MB, Baumann M, Berkowitz DV
Journal of Rheumatology. 2003;30(5):1070-1074
Scharf and colleagues report a double-blind, randomized, placebo-controlled cross-over trial of sodium oxybate in patients with fibromyalgia (FM). They evaluated the effects of sodium oxybate, a commercial form of gamma-hydroxybutyrate (GHB), on the subjective symptoms of pain, fatigue, and sleep quality and the objective polysomnographic sleep variables of alpha intrusion, slow-wave (stage 3/4) sleep, and sleep efficiency in patients with FM. They studied 24 female patients of which 18 completed the trial. The patients who dropped out were in the active medication portion of the study, and none of the side effects were considered serious events (transient episodes of headache, anxiety attack, or paresthesia).Journal of Rheumatology. 2003;30(5):1070-1074
In the intention-to-treat analysis of all patients who entered the protocol, tender-point index was decreased from baseline by 8.5, compared with an increase of 0.4 for the placebo (P = .0079) portion of the cross-over trial. Sodium oxybate was associated with relief of 29% to 33% of 6 of the 7 pain/fatigue scores (overall pain, pain at rest, pain during movement, end-of-day fatigue, overall fatigue, and morning fatigue), compared with relief of 6% to 10% with placebo (P < .005). Slow-wave (stage 3/4) sleep was significantly increased while alpha intrusion, sleep latency, and rapid eye movement (REM) sleep were significantly decreased compared with placebo (P < .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 = .0033) and quality of sleep (improved by 33% and 10%, respectively; P = .0003). The investigators conclude that sodium oxybate effectively reduced the symptoms of pain and fatigue in patients with FM, dramatically reduced the sleep abnormalities of alpha intrusion, and decreased slow-wave sleep associated with the characteristic nonrestorative sleep. This study is important for rheumatologists, because fatigue and fibromyalgia are common problems in our patients and a new effective class of drugs may improve functional outcome in FM patients.
FM is associated with alpha intrusion during sleep[1] and low growth hormone secretion.[2] Moldofsky and coworkers have demonstrated that alpha intrusion on the electroencephalogram (EEG) is a normal part of wakefulness; however, when it occurs too frequently in sleep, it is accompanied by daytime complaints of musculoskeletal pain, fatigue, and altered mood.[2,3] Although the mechanisms of sleep induction maintenance in normal individuals are poorly understood,[4] they are even more complex and multifactorial in patients with FM[2] and in patients with inflammatory processes associated with proinflammatory cytokines such as tumor necrosis factor.[5] In normal subjects, patients with FM or inflammatory conditions, and animal models, evidence for an increasingly important role for GHB has been accumulating.[6,7]
GHB is a naturally occurring metabolite of the human nervous system, with the highest concentration in the hypothalamus and basal ganglia. A commercial form of GHB has been developed as sodium oxybate. In healthy human volunteers, sodium oxybate has been shown to promote a normal sequence of non-REM and REM sleep for 2 to 3 hours. However, it is also important to recognize that GHB has gained wide recognition in the popular press as a "recreational drug" used for date rape[8,9] as it is tasteless and creates a sense of amnesia when taken with alcohol. Thus, GHB is both a therapeutic agent and a recreational drug. It has sedative, anxiolytic, and euphoric effects. These effects are believed to be due to GHB-induced potentiation of cerebral gamma-aminobutyric acid-ergic and dopaminergic activities, and recent studies suggest the serotonergic system might also be involved.[10] As the serotonergic system may be involved in the regulation of sleep, mood, and anxiety, the stimulation of this system may be involved in certain neuropharmacologic events induced by GHB administration.[10]
The biology of GHB may shed light on the important abnormality in sleep and the associated hypothalamic diurnal variations found in FM.[2,11] The potential importance of the study by Sharf and coworkers is that no medication has previously been shown to improve the EEG sleep arousal disorders that include phasic (alpha-delta), tonic alpha non-REM sleep disorders, or the periodic alpha cycling alternating pattern disorder.[12] Traditional hypnotic agents, while helpful in initiating and maintaining sleep and reducing daytime tiredness, do not provide restorative sleep or reduce pain. Tricyclic drugs, such as amitriptyline and cyclobenzaprine, may provide long-term benefit for improving sleep but may not have a continuing benefit beyond 1 month for reducing pain.
The basic balance between sleep and wakefulness has been an area of active interest in neurochemistry in recent years. There have been significant advances in understanding the molecular biology involved, largely based on studies of patients with narcolepsy and cataplexy. One emerging area of importance is the neuro-hormone hypocretin (orexin), whose deficiency (< 40 pg/mL) is highly associated with narcolepsy and cataplexy (89.5%).[13] In animal models of narcolepsy, the absence of hypothalamic orexin (hypocretin) neuropeptides leads to inability to maintain wakefulness and intrusion of REM sleep into wakefulness.[14] Absence of oxyrexen-2 receptor eliminates orexin-evoked excitation of histaminergic neurons in the hypothalamus, which gate non-REM sleep onset.
In summary, the article by Scharf and colleagues demonstrates that sodium oxybate improves functional status in fibromyalgia patients. This benefit may result from a significant reduction in the sleep abnormalities (alpha intrusion and diminished slow wave sleep) associated with the nonrestorative sleep that is a critical feature of FM. According to the authors, no other compound has been reported to reduce the alpha sleep abnormality. Although this abnormality is not specific to FM and its presence has not been distinguished as a cause or effect in FM, reducing alpha intrusion appears to correlate with clinical improvement.
References
Roizenblatt S, Moldofsky H, Benedito-Silva AA, Tufik S. Alpha sleep characteristics in fibromyalgia. Arthritis Rheum. 2001;44:222-230.Moldofsky HK. Disordered sleep in fibromyalgia and related myofascial facial pain conditions. Dent Clin North Am. 2001;45:701-713.
Moldofsky H, Lue FA, Shahal B, Jiang CG, Gorczynski RM. Diurnal sleep/wake-related immune functions during the menstrual cycle of healthy young women. J Sleep Res. 1995;4:150-159.
Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci. 2001;24:429-458.
Dickstein JB, Moldofsky H, Hay JB. Brain-blood permeability: TNF-alpha promotes escape of protein tracer from CSF to blood. Am J Physiol Regul Integr Comp Physiol. 2000;279:R148-R151.
Gamma hydroxybutyrate (Xyrem) for narcolepsy. Med Lett Drugs Ther. 2002;44:103-105.
Xyrem approved for muscle problems in narcolepsy. FDA Consum. 2002;36:7.
Tellier PP. Club drugs: is it all ecstasy? Pediatr Ann. 2002;31:550-556.
Smalley S. The perfect crime. Newsweek. February 3, 2003:141:52.
Gobaille S, Schleef C, Hechler V, Viry S, Aunis D, Maitre M. Gamma-hydroxybutyrate increases tryptophan availability and potentiates serotonin turnover in rat brain. Life Sci. 2002;70:2101-2112.
Scharf MB, Hauck M, Stover R, McDannold M, Berkowitz D. Effect of gamma-hydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with fibromyalgia. Preliminary report. J Rheumatol. 1998;25:1986-1990.
Brooks S, Black J. Novel therapies for narcolepsy. Expert Opin Investig Drugs. 2002;11:1821-1827.
Krahn LE, Pankratz VS, Oliver L, Boeve BF, Silber MH. Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA DQB1*0602 status. Sleep. 2002;25:733-736.
Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron. 2003;38:715-730.
Effect of gamma-hydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with fibromyalgia. Preliminary report.Scharf MB, Hauck M, Stover R, McDannold M, Berkowitz D Center for Research in Sleep Disorders, Cincinnati, Ohio, USA.
OBJECTIVE: To evaluate the effects of using a gamma-hydroxybutyrate (GHB) administered in divided doses at night in 11 patients previously diagnosed with fibromyalgia (FM). METHODS: 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.
RESULTS: 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. CONCLUSION: Further controlled studies are needed to characterize the clinical improvement and the polysomnographic changes we observed.
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GHB Report - Summary
Medical Uses
GHB is being used in other countries for many medical purposes. One of the purposes that deserves special mention is its use in France and Italy as an aid to childbirth. Its ability to calm maternal anxiety, protect against hypoxic injury to the baby, and accelerate dilation of the cervix (termed "spectacular" in one report) provide a graphic contraposition to allegations of toxicity, addiction and lethality.
It is rare to find a substance with as many applications to such a host of human maladies. Few medicines have as many beneficial actions upon the body as GHB for the prevention and treatment of debility and disease. Even fewer medicines have less side effects. The scientific and medical consensus on GHB established by conscientious laboratory and clinical investigation of the applications of GHB to enhance health and decrease suffering can only be sensationalized to a limited degree before all pretense at accuracy and honesty must be abandoned. It is unfortunate, but absolutely necessary, that we assess the rationale for SB3, SB54, and AB6 in light of this research.
Toxicity
GHB is fundamentally non-toxic.
GHB is fundamentally non-toxic.
Unlike alcohol, GHB has no general toxicity or organ toxicity. It is cleanly and quickly metabolized by the liver to carbon dioxide and water. Unlike alcohol, it does not kill brain cells and it does not cause cross-linking damage (an aging effect) to either tissues or skin (i.e., wrinkling). It does not cause cirrhosis of the liver. In 30 years of research, no long-term adverse effect has yet been identified.
These properties make GHB an excellent relaxation and sleep aid for pilots, truck drivers, factory workers and military personnel because of the rapidity at which it is cleared from the system and the complete lack of any lasting pharmacological effects. This can not be said for other sleep-aid drugs which are presently widely prescribed in the US.
What Effects Does GHB Cause?
In low doses (less than a gram), GHB is a mild relaxant. It causes a subtle drop in muscle tone and a mild relaxation of inhibitions (making people more sociable), very much like drinking a beer or glass of wine. This effect lasts for 1 or 2 hours.
In low doses (less than a gram), GHB is a mild relaxant. It causes a subtle drop in muscle tone and a mild relaxation of inhibitions (making people more sociable), very much like drinking a beer or glass of wine. This effect lasts for 1 or 2 hours.
In moderate doses (1-2 grams), GHB causes strong relaxation (mental and physical). This effect happens in 5-10 minutes on an empty stomach and 15-30 minutes on a full stomach (like with alcohol, food dramatically decreases the strength of the effect). GHB slows and deepens respiration (causing no net effect on blood gasses) and it slows heart rate, makes people passive, calm and possibly sleepy. There may be noticeable interference with articulation, motor coordination and balance. At this dose, the effects can last 2-3 hours.
In stronger doses (2-4 grams), interference with motor control and speech is more pronounced. The relaxation effect is quite strong, often causing sleepiness or sleep. The sleep induced by GHB is very deep, making it more difficult than would usually be expected to wake somebody. This state has been inappropriately labeled "coma" by some medical authorities with minimal concern for the popular perception of such an inflammatory term. Comas are technically defined as unarrousability, but the dangerous aspects of coma have to do with hypometabolism (inadequate production of biological energy) that interferes with normal mental function. During GHB-induced sleep, all the normal physiological sleep functions of the brain (stages 1, 2, 3 and 4, and REM) take place in a normal sequence.
The sleep-enhancing properties of GHB are potentially of immense value to society. GHB selectively deepens stage 3 and 4 sleep, which are most frequently impaired in the elderly. This is probably the mechanism by which GHB treats narcolepsy. This may also be the mechanism by which GHB increases growth hormone output (which normally takes place during the deepest stages of sleep). Not all people fall asleep on GHB. At the 2-4 gram dose range, GHB's effects last about 3-4 hours. At high doses (4-8 grams), powerful deep sleep is usually induced within 5-15 minutes on an empty stomach. The effect will sometimes last up to 4 hours. At extremely high doses (10-30 grams), the deep-sleep effects last for much longer periods. The highest reported GHB dose (termed a "poisoning" by the authors) involved a man who took an estimated 15 tablespoons of GHB! He woke up 24 hours later feeling groggy with a mild headache. He had no lasting effects.
GHB: Is it Lethal?
No. Everybody reported to have been "poisoned" with GHB has "fully recovered," even the man who took 15 tablespoons (50-75 grams?). There have been no long-term consequences identified in any of these cases despite close observation by attending physicians.
No. Everybody reported to have been "poisoned" with GHB has "fully recovered," even the man who took 15 tablespoons (50-75 grams?). There have been no long-term consequences identified in any of these cases despite close observation by attending physicians.
Although it is possible that somebody could ingest the 50-150 grams (2-5 ounces, 5 heaping tablespoons?) that might be expected to be life threatening, it is exceedingly difficult to do so. In high doses, GHB causes nausea and vomiting, which strongly limits the maximum amount that a person can consume. It is possible that a dedicated person wishing to commit suicide might be able to take a sleep-inducing dose of GHB and then, just before falling asleep, gulp down a huge amount of GHB, but this is not something which can be done accidentally. The sodium content alone (NaGHB is 17% sodium by weight) is enough to make somebody gag. It is the equivalent of trying to swallow 2 heaping tablespoons of pure table salt.
Can GHB Contribute to Death by other Causes?
We don't know. It is possible. But there is no supporting data with which to answer this question definitively. Like alcohol, GHB is contraindicated with CNS depressants. GHB should not be taken with alcohol, tranquilizers (benzodiazepines), sedatives (barbituates), or opiates (morphine, heroin, etc.). While GHB does not seriously suppress respiration by itself, CNS depressants do. Although it has not been measured, it is possible that GHB increases that respiratory suppression when combined with these drugs. Interestingly, GHB is being used clinically to treat drug addiction and drug withdrawal symptoms for CNS depressants and opiates. It is reported to be outstandingly effective for this use.
We don't know. It is possible. But there is no supporting data with which to answer this question definitively. Like alcohol, GHB is contraindicated with CNS depressants. GHB should not be taken with alcohol, tranquilizers (benzodiazepines), sedatives (barbituates), or opiates (morphine, heroin, etc.). While GHB does not seriously suppress respiration by itself, CNS depressants do. Although it has not been measured, it is possible that GHB increases that respiratory suppression when combined with these drugs. Interestingly, GHB is being used clinically to treat drug addiction and drug withdrawal symptoms for CNS depressants and opiates. It is reported to be outstandingly effective for this use.
Depression
Regarding the effect of increased levels of happiness, some US psychiatrists now prescribe GHB as an anti-depressant agent used during the day in several small doses. The reports have been noteworthy. Several report increased levels of happiness are sustained even when the person no longer has GHB in their system. Claude Rifat, a French biologist, reported, "GHB may be the first authentic anti-depressant. GHB suppresses depressed ideation with amazing rapidity.... (GHB) strongly stimulates the desire to be and remain alive despite unfavorable circumstances. Despair disappears, replaced by a feeling that life is worth living. GHB can suppress depression within hours. No conventional so called anti-depressant does that. Conventional antidepressants can takes weeks or months to alleviate suffering. GHB treatment is also very short; less than a month of treatment is usually effective, as opposed to months or years with other treatments." Increased levels of happiness may also be the result of the extended periods of deeper sleep and a more rested body.
Regarding the effect of increased levels of happiness, some US psychiatrists now prescribe GHB as an anti-depressant agent used during the day in several small doses. The reports have been noteworthy. Several report increased levels of happiness are sustained even when the person no longer has GHB in their system. Claude Rifat, a French biologist, reported, "GHB may be the first authentic anti-depressant. GHB suppresses depressed ideation with amazing rapidity.... (GHB) strongly stimulates the desire to be and remain alive despite unfavorable circumstances. Despair disappears, replaced by a feeling that life is worth living. GHB can suppress depression within hours. No conventional so called anti-depressant does that. Conventional antidepressants can takes weeks or months to alleviate suffering. GHB treatment is also very short; less than a month of treatment is usually effective, as opposed to months or years with other treatments." Increased levels of happiness may also be the result of the extended periods of deeper sleep and a more rested body.
Mental Enhancement
Mental clarity, perception and judgment all appear to improve with low dose use. Rapid eye movement sleep and protein synthesis - processes which may be linked, and both of which are facilitated by GHB - have been correlated with periods of intensive learning [Laborit, 1972]. GHB has also been shown to stimulate the release of acetylcholine, one of the brain's own intelligence and alertness boosting chemicals [Gallimberti, 1989]. Preliminary testing suggests improved reaction times and perceptual and cognitive reflexes with low dose use of GHB. These findings of increased alertness are surprising to those accustomed to expecting GHB to act solely as a sedative. Perhaps the answer lies in the fact that nature designed this molecule.
Mental clarity, perception and judgment all appear to improve with low dose use. Rapid eye movement sleep and protein synthesis - processes which may be linked, and both of which are facilitated by GHB - have been correlated with periods of intensive learning [Laborit, 1972]. GHB has also been shown to stimulate the release of acetylcholine, one of the brain's own intelligence and alertness boosting chemicals [Gallimberti, 1989]. Preliminary testing suggests improved reaction times and perceptual and cognitive reflexes with low dose use of GHB. These findings of increased alertness are surprising to those accustomed to expecting GHB to act solely as a sedative. Perhaps the answer lies in the fact that nature designed this molecule.
Full report prepared by Steven Wm Fowkes, Executive Director Cognitive Enhancement Research Institute Post Office Box 4029, Menlo Park, CA 94026 USA 650-321-CERI Fax: 650-323-3864
Email: fowkes@ceri.win.net Web: http://www.ceri.com/ http://www.win.net/ceri
Email: fowkes@ceri.win.net Web: http://www.ceri.com/ http://www.win.net/ceri
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GHB A GREAT HORMONE AT BEDTIME
Category: Neurochemistry Term Paper Code: 536
GHB is a natural metabolite manufactured by the human body and by many mammalian tissues in which it functions to increase dopamine levels in the body (Mamelak 1989). GHB can be found in many organs in the body such as the kidney, heart, skeletal muscles, and fat (Chin and Kreutzer 1992). Hypothalamus and basal ganglia in the brain are found to have the highest amount of GHB (Gallimberti 1989). GHB is believed to acts as a depressant to the central nervous system (WWW1) and a neurotransmitter or neuromodulator, and high affinity brain receptor that does not act on GABA receptor sites directly (Mamelak 1989; Chin and Kreutzer 1992).
The Action of GHB In sleeping situation, GHB can facilitate non rapid eye movement (NREM) and rapid eye movement (REM) sleep, the stage of sleep at which there is an increased release of growth hormone (Vickers 1969; Laborit 1972; Mamelak 1989). Mamelak (1989) has provided studies that "indicate GHB reduces energy substrate consumption in both the brain and the peripheral tissues, protects these tissues from the damaging effects of anoxia or excessive metabolic demand." "GHB may function naturally in the induction and maintenance of physiological states, like sleep and hibernation, in which energy utilization is depressed. GHB may also function naturally as an endogenous protective agent when tissue energy supplies are limited" (Mamelak 1989).
Vickers (1969) states that GHB sleep is characterized by increased levels of carbon dioxide in the arteries similar to normal sleep whereas the central nervous system continues to be responsive to stimuli such as pain and other irritations. Even though not everyone can be put to sleep by GHB, "sleep is deeper and more restful during the influence of GHB, and people tend to wake up after the GHB has worn off. There was speculation that this is related to the release of stored-up dopamine" (Laborit, 1972).
GHB temporarily inhibits the dopamine release in the brain, causing an increase in dopamine storage, and later increased release of dopamine when the GHB influence wears off (Chin and Kreutzer 1992). This could explain for the feelings of increased well-being, alertness and arousal afterward or the next day which are common with the use of higher GHB dosage. Dopamine activity in the hypothalamus is known to stimulate pituitary release of growth hormone (GH), but GHB inhibits dopamine release while stimulating GH release. This might be due to the fact that GHB's GH-releasing effect takes place through an entirely different mechanism (Takahara 1977). While GH is being released, the level of prolactin also rises. GHB decreases anxiety, achieves greater intensity and frequency of uterine contractions, increases sensitivity to oxytocic drugs (used to induce contractions), preserves reflexes, prevents the lack of respiratory depression in the fetus, and protects against fetal cardiac anoxia (Vickers 1969; Laborit 1964).
GHB activates a metabolic process referred to as the "pentose pathway" which plays an important role in protein synthesis within the body (Laborit 1972). It also causes a "protein sparing" effect (Laborit 1964) which reduces the rate at which proteins in the body is broken down. Respiration would become slower and deeper. GHB also stimulates the release of acetylcholine in the brain (Gallimberti 1989). Additionally, "GHB seems to act through the endogenous opioid system, in which dynorphin levels are raised by GHB in the brain, and its metabolic and pharmacological effects can be inhibited by naloxone" (Mamelak 1989).
Benefits and Applications GHB was found to be able to boost energy, cause pleasant and relax feelings, desire to socialize, enhance sexual experience, rejuvenate muscle and sleep, stimulate growth hormones (a steroid alternative) release (Steele and Watson 1995), relieve depression, and treat addiction. Research has been done to conclude that GHB was also primarily used to relieve and suppress withdrawal symptoms, cravings, and anxiety among alcoholics (Fadda 1989; Gallimberti 1989). "Most people experience relaxation and deep sleep within 45 minutes in response to 3.5g or less of GHB"
The Action of GHB In sleeping situation, GHB can facilitate non rapid eye movement (NREM) and rapid eye movement (REM) sleep, the stage of sleep at which there is an increased release of growth hormone (Vickers 1969; Laborit 1972; Mamelak 1989). Mamelak (1989) has provided studies that "indicate GHB reduces energy substrate consumption in both the brain and the peripheral tissues, protects these tissues from the damaging effects of anoxia or excessive metabolic demand." "GHB may function naturally in the induction and maintenance of physiological states, like sleep and hibernation, in which energy utilization is depressed. GHB may also function naturally as an endogenous protective agent when tissue energy supplies are limited" (Mamelak 1989).
Vickers (1969) states that GHB sleep is characterized by increased levels of carbon dioxide in the arteries similar to normal sleep whereas the central nervous system continues to be responsive to stimuli such as pain and other irritations. Even though not everyone can be put to sleep by GHB, "sleep is deeper and more restful during the influence of GHB, and people tend to wake up after the GHB has worn off. There was speculation that this is related to the release of stored-up dopamine" (Laborit, 1972).
GHB temporarily inhibits the dopamine release in the brain, causing an increase in dopamine storage, and later increased release of dopamine when the GHB influence wears off (Chin and Kreutzer 1992). This could explain for the feelings of increased well-being, alertness and arousal afterward or the next day which are common with the use of higher GHB dosage. Dopamine activity in the hypothalamus is known to stimulate pituitary release of growth hormone (GH), but GHB inhibits dopamine release while stimulating GH release. This might be due to the fact that GHB's GH-releasing effect takes place through an entirely different mechanism (Takahara 1977). While GH is being released, the level of prolactin also rises. GHB decreases anxiety, achieves greater intensity and frequency of uterine contractions, increases sensitivity to oxytocic drugs (used to induce contractions), preserves reflexes, prevents the lack of respiratory depression in the fetus, and protects against fetal cardiac anoxia (Vickers 1969; Laborit 1964).
GHB activates a metabolic process referred to as the "pentose pathway" which plays an important role in protein synthesis within the body (Laborit 1972). It also causes a "protein sparing" effect (Laborit 1964) which reduces the rate at which proteins in the body is broken down. Respiration would become slower and deeper. GHB also stimulates the release of acetylcholine in the brain (Gallimberti 1989). Additionally, "GHB seems to act through the endogenous opioid system, in which dynorphin levels are raised by GHB in the brain, and its metabolic and pharmacological effects can be inhibited by naloxone" (Mamelak 1989).
Benefits and Applications GHB was found to be able to boost energy, cause pleasant and relax feelings, desire to socialize, enhance sexual experience, rejuvenate muscle and sleep, stimulate growth hormones (a steroid alternative) release (Steele and Watson 1995), relieve depression, and treat addiction. Research has been done to conclude that GHB was also primarily used to relieve and suppress withdrawal symptoms, cravings, and anxiety among alcoholics (Fadda 1989; Gallimberti 1989). "Most people experience relaxation and deep sleep within 45 minutes in response to 3.5g or less of GHB"
Artru, A. A., Steen, P. A. and Michenfelder, J. D. Gamma-Hydroxybutyrate: Cerebral Metabolic, Vascular, and Protective Effects. Journal of Neurochemistry. 35(5): 1114-1119 (1980). Chin, M. Y., Kreutzer, R. A. and Dyer, J. E. Acute poisoning from gamma-hydroxybutyrate in California. West Journal of Medicine (United States) 156(4): 380-384 (1992). Chin, R. L. et al. Clinical course of gamma-hydroxybutyrate overdose. Annals of Emergency Medicine 31(6): 716-722 (1998). Fadda, F. et al. Suppression by gamma-hydroxybutyric acid of ethanol withdrawal syndrome in rats. Alcohol and Alcoholism (Great Britain) 24(5): 447-451 (1989). Ferrara, S. D. et al. Fatality due to gamma-hydroxybutyric acid (GHB) and heroin intoxication. Journal of Forensic Science 40(3): 501-504 (1995). Gallimberti, L. et al. Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome. The Lancet, 787-789 (1989). Kam, P. C. & Yoong, F. F. Gamma-hydroxybutyric acid: an emerging recreational drug. Anaesthesia 53(12): 1195-1198 (1998). Laborit, H. Correlations between protein and serotonin synthesis during various activities of the central nervous system (slow and desynchronized sleep, learning and memory, sexual activity, morphine tolerance, aggressiveness, and pharmacological action of sodium gamma-hydroxybutyrate). Research Communications in Chemical Pathology and Pharmacology 3(1) (1972). Laborit, H. Sodium 4-Hydroxybutyrate. Int Journal of Neuropharmacology (Great Britain) 3: 433-452 (1964). Mamelak, M. Gammahydroxybutyrate: an endogenous regulator of energy metabolism. Neuroscience Biobehav Rev 13(4): 187-198 (1989).
Park, S. et al. GHb is a better predictor of cardiovascular disease than fasting or postchallenge plasma glucose in women without diabetes. The Rancho Bernardo Study. Diabetes Care 19(5): 450-456 (1996). Steele, M. T. & Watson, W. A. Acute poisoning from gamma hydroxybutyrate (GHB). Mo Medicine 92(7): 354-357 (1995). Takahara, J. et al. Stimulatory effects of gamma-hydroxybutyric acid on growth hormone and prolactin release in humans. Journal of Clinical Endocrinalogical Metabolism 44: 1014 (1977). Vickers, M.D. Gamma-hydroxybutyric Acid. Int Anaesthesia Clinic 7: 75-89 (1969).
Viera, A. J. & Yates, S. W. Toxic ingestion of gamma-hydroxybutyric acid. South Medical Journal 92(4): 404-405 (1999).
Park, S. et al. GHb is a better predictor of cardiovascular disease than fasting or postchallenge plasma glucose in women without diabetes. The Rancho Bernardo Study. Diabetes Care 19(5): 450-456 (1996). Steele, M. T. & Watson, W. A. Acute poisoning from gamma hydroxybutyrate (GHB). Mo Medicine 92(7): 354-357 (1995). Takahara, J. et al. Stimulatory effects of gamma-hydroxybutyric acid on growth hormone and prolactin release in humans. Journal of Clinical Endocrinalogical Metabolism 44: 1014 (1977). Vickers, M.D. Gamma-hydroxybutyric Acid. Int Anaesthesia Clinic 7: 75-89 (1969).
Viera, A. J. & Yates, S. W. Toxic ingestion of gamma-hydroxybutyric acid. South Medical Journal 92(4): 404-405 (1999).
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Data on Xyrem® (sodium oxybate) presented at the American College of Rheumatology
Orange, CA - November 17, 2005
The data from an eight-week study will be presented today at the annual meeting of the American College of Rheumatology in San Diego.
"These results are very exciting because - for the first time - we have results that provide evidence that a product which improves the quality of sleep during the night also has a dramatic effect on reducing pain," said the study's lead researcher, I. Jon Russell, M.D., Ph.D. associate professor of medicine at the University of Texas Health Science Center in San Antonio and a member of the NFA's Medical Advisory Board. "Both pain and losses of sleep are significant issues faced by patients suffering from fibromyalgia syndrome."
Fibromyalgia (FM) is a complex chronic pain illness that can lead to significant patient disability. The fact that there is no known cause or cure for fibromyalgia challenges patients and healthcare professionals alike. It is estimated that FM affects approximately six to eight million Americans and 5% of the world's population. Patients with fibromyalgia suffer from a variety of symptoms ranging from stiffness, muscle spasms and body wide pain, fatigue and severe sleep disturbances.
"This study will provide significant hope for patients searching for ways to effectively manage the chronic pain of this severe disorder," said Lynne Matallana, president and founder of the National Fibromyalgia Association. "The NFA is very excited to support research that examines new treatment options for fibromyalgia."
Xyrem, marketed by Orphan Medical, Inc., a subsidiary of Jazz Pharmaceuticals, was approved by the U.S. Food and Drug Administration (FDA) in October 2002 as the first and only treatment for cataplexy (sudden loss of muscle tone) in patients with narcolepsy.
The Study
- Significant benefit in the primary outcome variable (POV) was seen with both doses of sodium oxybate compared with placebo [illustrated by 4.5g, p=0.005].
- Sleep quality [SLP] was improved with both dosages of oxybate [4.5g, p=0.004].
- A significant correlation was seen between change in pain and change in sleep quality [r=0.55, p<0.001].
- In this study, sodium oxybate was shown to be well tolerated, as illustrated by the high rate of study completion.
- In the study, the most commonly reported adverse events included nausea and dizziness and were dose-related [4.5g, 15% and 6.7%, respectively; placebo, 9.2% and 1.5%].
Methodology
Dr. Russell and his colleagues, Drs. Robert M. Bennett in Portland and Joel E. Michalek in San Antonio, conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial. The centers initially recruited 188 patients [placebo, n=64; oxybate 4.5g, n=58; oxybate 6g, n=66], of whom 147 [78%] completed the trial. One group took 4.5 grams of sodium oxybate per day, while a second group took 6 grams per day. The sodium oxybate was administered orally twice a day. The POV was a composite of changes from baseline in three co-primary, self-report measures: Pain Visual Analog Scale [PVAS], captured with electronic diaries; Fibromyalgia Impact Questionnaire [FIQ]; and Patient Global Assessment [PGA]. Secondary outcome measures included changes in sleep quality [SLP]. The trial lasted eight weeks.
"These results show significant improvements when compared to placebo in the patient's sleep quality as well as the reduction of the patient's pain," stated Dr. Russell.~~~~~~~~~~~~~~~~~~~~
10/03/2006 XYREM® LICENSE AGREEMENT TO INCLUDE FIBROMYALGIA SYNDROME
UCB also adds new marketing territories under expanded agreement --
Brussels, Belgium and Palo Alto, California – October 3rd 2006 – UCB (Euronext Brussels: UCB) and Jazz Pharmaceuticals, Inc. today announced the signing of an expanded product license agreement for Xyrem® (sodium oxybate).
Under the agreement, UCB obtains the right to commercialize Xyrem for the treatment of fibromyalgia syndrome, if and when the product is approved for this indication. On September 7, 2006, Jazz Pharmaceuticals announced the initiation of its Phase III clinical development program evaluating the use of Xyrem for the treatment of fibromyalgia syndrome.
In addition, the agreement doubles, from 27 to 54, the number of countries in which UCB has commercialization rights to Xyrem. Jazz Pharmaceuticals markets Xyrem in the United States. Commenting on the new agreement William Robinson, Executive Vice President, Global Operations, UCB said, “Fibromyalgia is an under-diagnosed, under-treated condition and we are encouraged on the initiation of the Phase III trial to evaluate Xyrem as a treatment for this chronic pain illness. Acquiring the rights to in-licence Xyrem for fibromyalgia syndrome demonstrates the ongoing commitment of UCB to satisfying unmet medical needs.” He continued, “We also look forward to making Xyrem available to narcolepsy patients in many more countries.”
Under the expanded agreement, UCB has made an upfront payment and will make milestone payments to Jazz Pharmaceuticals, subject to future clinical development and sales results. UCB will also pay royalties to Jazz Pharmaceuticals on Xyrem sales across the 54 agreed territories. “We are pleased to announce the significant expansion of our commercial partnership with UCB for Xyrem, which will bring this important therapy to patients in many more countries,” said Robert M. Myers, Chief Business Officer of Jazz Pharmaceuticals. “We look forward to continuing the investigation of the clinical utility of Xyrem for the treatment of fibromyalgia syndrome.”
Brussels, Belgium and Palo Alto, California – October 3rd 2006 – UCB (Euronext Brussels: UCB) and Jazz Pharmaceuticals, Inc. today announced the signing of an expanded product license agreement for Xyrem® (sodium oxybate).
Under the agreement, UCB obtains the right to commercialize Xyrem for the treatment of fibromyalgia syndrome, if and when the product is approved for this indication. On September 7, 2006, Jazz Pharmaceuticals announced the initiation of its Phase III clinical development program evaluating the use of Xyrem for the treatment of fibromyalgia syndrome.
In addition, the agreement doubles, from 27 to 54, the number of countries in which UCB has commercialization rights to Xyrem. Jazz Pharmaceuticals markets Xyrem in the United States. Commenting on the new agreement William Robinson, Executive Vice President, Global Operations, UCB said, “Fibromyalgia is an under-diagnosed, under-treated condition and we are encouraged on the initiation of the Phase III trial to evaluate Xyrem as a treatment for this chronic pain illness. Acquiring the rights to in-licence Xyrem for fibromyalgia syndrome demonstrates the ongoing commitment of UCB to satisfying unmet medical needs.” He continued, “We also look forward to making Xyrem available to narcolepsy patients in many more countries.”
Under the expanded agreement, UCB has made an upfront payment and will make milestone payments to Jazz Pharmaceuticals, subject to future clinical development and sales results. UCB will also pay royalties to Jazz Pharmaceuticals on Xyrem sales across the 54 agreed territories. “We are pleased to announce the significant expansion of our commercial partnership with UCB for Xyrem, which will bring this important therapy to patients in many more countries,” said Robert M. Myers, Chief Business Officer of Jazz Pharmaceuticals. “We look forward to continuing the investigation of the clinical utility of Xyrem for the treatment of fibromyalgia syndrome.”
About Fibromyalgia
Fibromyalgia is a chronic pain illness which is characterized by widespread musculoskeletal aches, pains and stiffness, soft tissue tenderness, general fatigue and sleep disturbances. The most common sites of pain include the neck, back, shoulders, pelvic girdle and hands, but any body part can be involved.
About Xyrem in Europe1
In 2005, Xyrem became the first and only medication approved by the European Medicines Agency (EMEA) for the treatment of cataplexy in adult patients with narcolepsy, and the product has since been launched for this indication in Denmark, Germany, Norway and the UK. In April 2006, UCB filed an application with the EMEA seeking marketing approval for the use of Xyrem in the treatment of narcolepsy in adult patients. The application spans all symptoms of narcolepsy, including excessive daytime sleepiness and fragmented night-time sleep. The most commonly reported adverse drug reactions are dizziness, nausea, and headache, all occurring in 10 % to 20 % of patients. Sodium oxybate is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. Sodium oxybate is contraindicated in patients being treated with opioids or barbiturates.
Jazz Pharmaceuticals Mark Leonard 847-267-9660 markdleonard@comcast.net Jazz Pharmaceuticals, Inc. Matthew Fust Chief Financial Officer 650-496-3777 mediainfo@jazzpharma.com
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