Gamma Hydroxybutyrate

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Gamma-Hydroxybutyrate (GHB) is produced naturally by the body in small quantities, however its exact physiologic function is not known. It can also be manufactured synthetically, which was first done in the 1960s under experimental conditions. It was later classified as a food and dietary supplement and was available for purchase in health food stores in the early 1990s. However, in the late 1990s, the US Food and Drug Administration (FDA) banned over-the-counter sales of GHB in the United States, and also issued warnings related to the dangers of its precursor drugs (chemicals used in the manufacture of GHB) – GBL and 1,4-BD. In 2000, GHB was reclassified by the FDA as a Schedule I controlled substance, meaning that it has a high potential for abuse, has no currently accepted medical use in treatment, and has a lack of accepted safety data supporting the use of the drug under medical supervision.

For comparison, examples of other Schedule I drugs include heroin, LSD, marijuana, peyote, and ecstasy. Despite this increased regulation, GHB continues to be available from suppliers over the Internet, in the form of make-it-yourself kits. Its precursor drugs were also reclassified as controlled substance analogs, which essentially renders them a Schedule I controlled substance in situations where they are intended for human consumption. Outside of this realm, both GBL and 1,4-BD are commercially available and used as industrial solvents, as well as ingredients in cleaners, other solvents, paint removers, and engine degreasers. Furthermore, they are also marketed on the Internet and in some health food stores as “natural” and “non-toxic” dietary supplements. Currently, a type of GHB, known as sodium oxybate (Xyrem®) has FDA approval as an orphan drug, meaning it is approved for use in extremely rare conditions. Xyrem® is approved for use in treating narcolepsy (excessive daytime sleepiness) as well as to reduce cataplexy (attacks of muscle weakness and paralysis) in individuals with narcolepsy.

GHB acts as a central nervous system depressant, and also has sedative and anesthetic properties. It appears to affect dopamine levels in the brain. Among its medical uses, GHB has been used in Europe as both an anesthetic and a hypnotic agent, as well as a treatment for narcolepsy (periods of excessive daytime sleepiness) and to alleviate the symptoms of withdrawal among individuals who are addicted to alcohol or opiate pain medications. GHB is frequently used illicitly to induce euphoria (i.e., “get high”), reduce inhibitions, and promote sedation. It is also one of the drugs commonly referred to as a “date rape drug.” It is popular among young adults and teenagers in night club and party environments. Furthermore, some bodybuilders use GHB in lieu of anabolic steroids, as it promotes the natural release of growth hormone in the body. Its precursors are rapidly converted into GHB once consumed into the body, and are commonly marketed to consumers as anti-aging drugs, weight-loss aids, as well as treatments for insomnia, anxiety, depression, and as mood stabilizers. GHB is most often consumed in oral form, either as a powder that is dissolved in water or alcohol, or as a liquid that is sold in small vials. The average dose consumed for illicit purposes is between one to five grams, and cost ranges from $5 to $10.

GHB exerts a number of effects on the body following ingestion. At low doses, it mimics the effects of alcohol, including relaxation, reduced inhibitions, euphoria, confusion, dizziness, drowsiness, sedation, “drunkenness,” aggression, and even hallucinations. Physical effects of GHB can include nausea, vomiting, extensive sweating, daytime sleepiness, vision disturbances including involuntary eye movements and loss of peripheral vision, short-term memory loss, seizures, abnormal heart rhythms, decreased body temperature, decreased respiration, and loss of consciousness. Deaths have also been reported in relation to overdoses of GHB, as well as its precursor drugs GBL and 1,4-BD. The effects of GHB typically start within 10 to 20 minutes following ingestion, and generally last for between two and five hours. Tolerance can also develop to GHB following chronic illicit abuse, as well as with chronic treatment, and withdrawal symptoms also occur. These may include mild anxiety, confusion, agitation, tremor, muscle cramping, insomnia, aggression, delirium, paranoia with hallucinations, heart rhythm disturbances, low blood pressure, and schizophrenia-like symptoms. GHB has the potential to interact negatively with other sedation-inducing central nervous system depressants, including alcohol, antidepressant medications, antipsychotic medications, antihistamines, and muscle relaxants.

GHB and Fibromyalgia

A 1998 study evaluated the effects of GHB in 11 fibromyalgia patients. Patients were administered GHB at night in divided doses, and completed daily diaries to assess their pain and fatigue. In addition, patients completed laboratory sleep studies before the study and one month after the initiation of treatment with GHB. During these studies, their sleep stages and sleep quality were measured. The researchers found significant improvements in pain and fatigue, as well as improvements in sleep patterns (Scharf et al., 1998).

Additional studies have been conducted investigating the usefulness of sodium oxybate (Xyrem®) in treating fibromyalgia-related symptoms. A recent study by Spaeth and colleagues evaluated the effects of sodium oxybate on fibromyalgia-associated pain and other symptoms. A total of 573 fibromyalgia patients, all diagnosed according to the 1990 American College of Rheumatology (ACR) criteria, were enrolled in the study from a total of eight countries. Each subject was randomly assigned to receive one of three treatments: sodium oxybate 4.5g/night, sodium oxybate 6 g/night, or a placebo over a 14 week course of treatment. At the end of the study, the researchers found that those who received sodium oxybate showed significant reductions in pain severity. Those who received 4.5/g night experienced a 42% reduction in pain, whereas those who received the 6 g/night dose experienced a 51.4% reduction in pain. For comparison, those in the placebo group only experienced a 26.8% reduction. Furthermore, some individuals experienced significant reductions in pain as early as one week after the start of treatment. In addition, individuals who received sodium oxybate also experienced improvements in tender point count and severity, fatigue, overall functioning, and sleep quality. The authors conclude their discussion by noting the association between improved sleep quality and fibromyalgia symptoms, and suggest that improving sleep quality should be a therapeutic goal for fibromyalgia patients (Spaeth et al., 2012).

A similar study was conducted across 74 sites in the United States. In total, 548 fibromyalgia patients (all of whom met ACR diagnostic criteria) were randomly assigned to received sodium oxybate in either a 4.5g or 6.0g/night doses, or one of two placebo doses. Those in the sodium oxybate groups all started at 4.5g per night. After two weeks of treatment, those randomized to receive the 6.0g/night dose had their doses increased. Treatment continued for an additional 12 weeks, for a total treatment period of 14 weeks. Researchers found significant improvements in pain severity for those who received either dose of sodium oxybate versus those in the two control groups. The two doses demonstrated relatively identical benefit: those receiving 4.5/g experienced a 54.2% improvement in pain severity versus 58.5% for those in the 6.0g group. Placebo groups received only a 35.2% improvement. Reductions in tender point counts were found for only those treated at the 4.5g dose, however improvements in tender point sensitivity were lower for both groups treated with sodium oxybate. In addition, the researchers also found significant improvements in fatigue, sleep disturbance, and overall functioning among those treated with sodium oxybate versus those who received placebo doses (Russell et al., 2011). A previous study also led by Dr. Russell and conducted across 21 sites in the United States also obtained similar findings (Russell et al., 2009).

An earlier study by Moldofsky et al., (2010) evaluated 304 fibromyalgia patients in an eight week study, using sodium oxybate doses 4.5g/night and 6.0g/night, as well as placebo. These researchers also found significant improvements in sleep patterns and sleep-related fibromyalgia symptoms, including daytime sleepiness, fatigue, and daytime functioning (Moldofsky et al., 2010). Other authors have reported similar findings (Scharf et al., 2003).

Based on these encouraging findings, the manufacturer of Xyrem®, Jazz Pharmaceuticals, applied for FDA approval of the drug to treat fibromyalgia in 2010. Although the FDA acknowledged that previous studies, including those described above, had demonstrated efficacy of Xyrem® for treating fibromyalgia-related pain, they disagreed with data that suggested sodium oxybate had a beneficial impact on sleep. Based on a 20-2 vote against approval by the reviewing FDA Advisory Panel, the FDA ultimately did not approve Xyrem® as a treatment for fibromyalgia. The Panelists cited a lack of convincing effectiveness, and concerns regarding potential risks associated with the drug. Furthermore, they pointed out a lack of information regarding potential drug interactions with other medications, as well as the extremely high risk of misuse and addiction.

Some Fibromyalgia advocates have pointed out that other drugs approved for the treatment of Fibromyalgia did not exhibit benefits as strong or clear as GHB and also had significant side effect risks. They argue that the Government is more concerned about preventing some individuals from possibly abusing a drug than providing access to effective treatment options for individuals who need it.

Regardless of how effective it may be and what its potential to help is for many patients, due to US Government restrictions GHB based treatment options remain unavailable for those suffering from Fibromyalgia inside the United States.

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References

1.        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(10):1986-1990.

2.        Spaeth M, Bennett RM, Benson BA, Wang YG, Lai C, Choy EH. Sodium oxybate therapy provides multidimensional improvement in fibromyalgia: results of an international phase 3 trial. Ann Rheum Dis. 2012;doi:10.1136/annrheumdis-2011-200418.

3.        Russell IJ, Holman AJ, Swick TJ, Alvarez-Horine S, Wang YG, Guinta D, for the Sodium Oxybate 06-008 FM Study Group. Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: results from a 14-wee, randomized, double-blind, placebo-controlled study. Pain. 2011;152(5):1007-1017.

4.        Russell IJ, Perkins AT, Michalek JE: Oxybate SXB-26 Fibromyalgia Syndrome Study Group. Sodium oxybate relieves pain and improves function in fibromyalgia syndrome: a randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 2009;60(1):299-309.

5.        Moldofsky H, Inhaber NH, Guinta DR, Alvarez-Horine SB. Effects of sodium oxybate on sleep physiology and sleep/wake-related symptoms in patients with fibromyalgia syndrome: a double-blind, randomized, placebo-controlled study. J Rheumatol. 2010;37(10):2156-2166.

6.        Scharf MB, Baumann M, Berkowitz DV. The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia. J Rheumatol. 2003;30(5):1070-1074.

7.        McMillen M. FDA Panel Rejects Xyrem as Fibromyalgia Treatment. WebMD Health News. http://www.webmd.com/fibromyalgia/news/20100820/fda-panel-rejects-xyrem-as-fibromyalgia-treatment  August 20, 2010; Accessed April 24, 2012.

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