Sodium oxybate is a promising new alternative treatment to the stimulants, hypnotics, and tricyclic antidepressants that were previously prescribed for narcolepsy.
Narcolepsy is a profoundly disabling, life-long sleep disorder characterized by excessive daytime sleepiness (hypersomnia), often in association with cataplexy. Narcolepsy has an estimated prevalence in the United States of between one in 2,000 and one in 100,000 depending on the population studied. This prevalence is similar to that of multiple sclerosis or Parkinson’s disease. It is estimated that only 25% of narcolepsy patients have been diagnosed to date.
Etiology of Narcolepsy
Two recent advances have occurred in understanding the causes of narcolepsy:
- Genetic predisposition. About 95% of narcolepsy/cataplexy patients appear to have a genetic predisposition for narcolepsy associated with a specific HLA (human leukocyte antigen) type, HLA-DQB1*0602. An environmental trigger may also be involved.1
- Hypocretin (also called orexin) neurochemical deficiency. The brain and cerebrospinal fluid of more than 90% of narcoleptic subjects are almost completely deficient in the neuropeptide.2
Narcolepsy is the manifestation of abnormal boundaries between sleeping and waking. Normally, the regulation of sleep vs wake is mediated by two hypothalamic neural pathways. A GABA system arising in the ventrolateral preoptic nucleus promotes sleep by inhibiting an ascending arousal system. A hypocretin/orexin system promotes waking by activating the ascending arousal system. In animal models, destruction of the GABA system causes insomnia; destruction of the hypocretin/orexin system causes classic symptoms of narcolepsy.
The current hypothesis for the cause of human narcolepsy proposes that an HLA-linked autoimmune response may damage hypocretin neurons, rendering them unable to maintain alertness and phasic muscle tone, resulting in the uncontrollable sleepiness of narcolepsy plus the intrusion of rapid eye movement (REM) into wakefulness. One REM manifestation is atonia of the skeletal muscles, which, if it occurs during waking, constitutes cataplexy.
A lack of awareness of narcolepsy may lead to a delay in diagnosis and inappropriate treatment. Narcolepsy patients have been initially misdiagnosed with other conditions including epilepsy, schizophrenia, chemical dependence, or sleep apnea. Since the age of onset of narcolepsy is typically between 15 and 45 years old, a delay in diagnosis or a misdiagnosis may have disastrous psychosocial consequences. These consequences include difficulties in school or on the job, as well as problems maintaining social life and interpersonal relationships. A study of the quality of life among narcoleptics found their score similar to that of Parkinson’s disease patients. The lowest scores were for role limitations and vitality.3
Narcolepsy is characterized by:
- fragmented sleep
- excessive daytime sleepiness
- irresistible “sleep attacks”
- abnormal REM sleep boundaries resulting in the intrusion of REM characteristics into wakefulness. Manifestations of the blurring of REM sleep boundaries include: cataplexy, sleep paralysis, and hypnagogic/pompic hallucinations.
During normal REM sleep, motor atonia prevents the sleeper from “acting out” dreams. Cataplexy is the abnormal occurrence of REM motor atonia during the waking state. The other two abnormal REM phenomena, sleep paralysis and hypnagogic/pompic hallucinations, occur when REM appears during the transitions at sleep onset and upon awakening, respectively.
Cataplexy: Fighting Gravity
Cataplexy is embarrassing, disruptive, and burdensome to manage. Cataplectic episodes may occur many times daily, depending on severity. They typically are triggered by strong emotion, such as laughter, joking, anger, excitement, surprise, stress, and even the anticipation or recollection of an emotional event. The typical narcoleptic patient with cataplexy learns to wear an emotional straitjacket in an effort to stave off an episode.
In a cataplectic attack, REM atonia may affect skeletal muscles to varying degrees, progressing from the head and neck downward to limb muscles. The eyes may close, the head or jaw may sag, speech may become slurred, hands may loosen their grip, or the knees may buckle. Cataplexy can sometimes be subtle in its presentation, but severe episodes can occur and may progress to complete collapse. One third of narcolepsy/ cataplexy patients report injury from such a collapse.
The duration of a cataplectic episode generally is a few seconds to several minutes, during which time the individual usually is fully conscious and medically stable. Cataplectic episodes resolve spontaneously. Narcolepsy patients are not hyper-reflexic after an episode of cataplexy, which is in contrast to a postictal state following a generalized seizure.
Narcolepsy: Fighting Sleep
Narcoleptics fight a constant battle against sleepiness. Narcoleptics typically score above 15 on the Epworth Sleepiness Scale (ESS), a subjective rating of daytime sleepiness. An ESS score above 10 indicates abnormal sleepiness. On the Multiple Sleep Latency Test (MSLT), an objective measure of the tendency to fall asleep, the narcoleptic’s tendency to fall asleep is equivalent to a normal person’s score after a full night without sleep.4
No single medication has been available to treat the spectrum of narcolepsy symptoms. Physicians have had to balance several conflicting medications including stimulants to improve daytime wakefulness, hypnotics to improve nighttime sleep, tricyclic antidepressants, or selective serotonin reuptake inhibitors to combat cataplexy and other REM-related symptoms. None of these drugs is ideally effective and all may have serious adverse side effects, including tolerance, withdrawal, and symptom rebound.
Sodium oxybate (gammahydroxybutyrate [GHB]) is a naturally occurring neurotransmitter substance that has been used in Europe since the 1960s as an anesthetic. During the 1990s, several double-blind trials5,6 in the United States reported that sodium oxybate improved nighttime sleep, daytime alertness, and the REM-related symptoms of narcolepsy.
A 24-year-old woman who presented for the evaluation of hypersomnia had onset at age 15. The hypersomnia persisted despite the fact that she was sleeping 6 to 8 hours during the week and 10 to 11 hours on the weekends. She woke up at 7 am on workdays and at 8:30 am on weekends. She had a difficult time maintaining wakefulness while reading or using the computer at work. It was difficult to develop a social life because she often went to bed early on weekends to catch up on her sleep.
She had vivid and disturbing dreams throughout the sleep cycle but rapidly got back to sleep after they occurred. She did not have complex nocturnal behaviors. She had sleep paralysis once or twice a month and this was long-standing. She napped whenever she had the opportunity and the restorative nature of the naps had optimized if she slept only 20 to 30 minutes. If she slept longer, the naps tended to be more sedating than alerting. She had frequent hypnagogic hallucinations with her naps and had difficulty clearly perceiving the sleep/wake transition. She had recurrent episodes of cataplexy that tended to cluster with multiple episodes during 1 week and few episodes in another week. If she laughed or got excited, she felt that her neck muscles were getting weak and she would sit down and be overcome by the irresistible urge to sleep. During these episodes she was able to hear everything that was going on around her but was unable to participate. Typically, these episodes lasted a few minutes.
She had no history of seizure disorder or psychiatric illness. There was no history of head trauma or other known neurologic disease risk factors.
She underwent an overnight sleep study that demonstrated an apnea-hypopnea index of 0.4 events per hour. She slept for 7.2 hours with a sleep efficiency of 95% and a shortened sleep latency of 3 minutes. Her REM onset latency was 45 minutes. She had six cycles of REM sleep, all of which were truncated. This was followed by nap testing with five naps with a mean sleep latency of 3.5 minutes and REM sleep occurring after 8 minutes in nap two and after 3 minutes in nap five.
She was started on methylphenidate in divided doses with a maximum of 60 mg/day because of persistent hypersomnia, but developed jitteriness, which precluded further use of that medication. She was also started on fluoxetine for cataplexy but was unable to tolerate this medication because of a decrease in libido and other side effects.
Ultimately, she was started on GHB at 3 mg in two nightly divided doses and tolerated this well with improvement in sleep continuity and resolution of cataplexy. She has also been started on dextroamphetamine at a total dose of 20 mg a day to augment her daytime function. These medications have been well tolerated and her ability to stay awake at work and at home in the evenings is greatly improved.
Sodium Oxybate Study
Sodium oxybate is a metabolite of GABA, and is completely and rapidly metabolized into carbon dioxide and water with no intermediary metabolites. It is very fast-acting, with maximum concentrations reached in 35 to 40 minutes, and terminal half-life of about 50 minutes.7 For all-night effectiveness the recommended regimen is two doses nightly, taken 2.5 to 4 hours apart.
The mode of action of sodium oxybate is not well understood. It appears to bind to the GABAB receptor. Cataplexy and REM sleep are regulated by dual systems, one cholinergic, which activates REM, the other adrenergic and serotonergic systems, which deactivate REM.
Presumably, sodium oxybate plays a hypocretin-supporting role in inhibiting the sleep-promoting actions of the GABA system, while preventing the intrusion of REM atonia and its resulting cataplexy.
A recent set of 14 trials by the United States Xyrem® Multicenter Study Group (double blind, placebo-controlled, N=408, C=125) confirmed the results of earlier studies. One of those recent multicenter studies, comparing different dosages of oral liquid sodium oxybate, reported the following results8:
- Cataplexy. Significantly diminished the number of cataplexy episodes (% change from baseline)
- -49% at 6-g dose.
- -69% at 9-g dose, P=0.0008).
This effect on cataplexy became even more striking in a 12-month open label extension trial. By the sixth month, all doses (3 g through 9 g) had reduced the daily median number of cataplexy episodes by 80% to 100% (see Figure).
Figure. Median percent change from baseline for cataplexy
attacks per week by sodium oxybate dose.8
Cessation of therapy resulted in the return of cataplexy within 2 weeks.
- Alertness. A 9-g dose significantly improved daytime ESS score compared with placebo (P=0.0001), and brought the ESS scores for some patients into the normal range. This effect was maintained during the 12-month open label extension trial.
- Sleep attacks. Significant reduction in the number of sleep attacks at both the 6-g dose (P=0.0497) and the 9-g dose (P=0.0122).
- Nighttime sleep. Significant decrease in the number of nighttime awakenings and increase in Stages 3 and 4 sleep at the 9-g dose (P=0.0035).
- Quality of life. The Clinical Global Impression of Change improved from baseline in a dose-related manner. Significant improvement at the 9-g dose (P=0.0002).
Adverse Events and Abuse Issues
The most common adverse effects of sodium oxybate at the 9-g dose were: dizziness (34%), nausea (34%), headache (31%), incontinence (14%), confusion (14%), and vomiting (11%) (Xyrem trial). Some of these side effects abated over the course of the trials. No evidence of tolerance, dose escalation, withdrawal syndrome, or rebound were reported at therapeutic doses.
Sodium oxybate, formerly known as GHB, has a history of abuse. In the 1980s health food stores sold it as a nutritional supplement, but over-the-counter sales were prohibited in 1990 because of reports of abuse and addiction. In the 1990s GHB gained a negative reputation as the “date rape” drug. It may act on the same receptor as flunitrazepam, a fast-acting sedative/anxiolytic. Sodium oxybate, diluted with alcohol or water, produces mild euphoria at low doses and deep sleep at higher doses. These characteristics have led to some 5,000 overdoses and 66 deaths over several years according to the Drug Enforcement Administration. The most serious cases appear to have involved mixtures with alcohol or opiates.9
In March 2000, GHB was classified as a Schedule I controlled substance; however, a provision makes it a Schedule III drug if it is used for a Food and Drug Administration (FDA) approved indication. Sodium oxybate is now approved by the FDA for treatment of cataplexy. It is distributed through a restricted program utilizing a single pharmacy and a physician education program.
Narcolepsy is an under-recognized, disabling neurologic disease that responds well to treatment. Recent research is elucidating the pathophysiology of this disease. Sodium oxybate is a novel medication for the treatment of narcolepsy with cataplexy. Regarding side effects at therapeutic dosage, as well as the potential for tolerance, dose escalation, or withdrawal, sodium oxybate is a promising new adjunct or alternative treatment to the stimulants, hypnotics, and tricyclic antidepressants historically prescribed for narcolepsy.
Daniel Loube, MD, is associate director; Ralph Pascualy, MD, is director; and Sally Soest, MS, is a medical writer, all at the Swedish Medical Center, Seattle.
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