Out of the Pipeline
Sodium oxybate: A new way to treat narcolepsy
A legally manufactured drug with an illegal form has been shown to reduce cataplexy episodes by improving nighttime sleep.
Existing drug treatments for narcolepsy enhance daytime alertness, and most improve cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations. None of these agents, however, target the nocturnal sleep deficits that lead to daytime symptoms.
Sodium oxybate, one of the most controversial medications to receive FDA approval in recent years (Table 1), has been found to reduce daytime sleepiness and cataplexy by improving nighttime sleep in patients with narcolepsy.
ABOUT SODIUM OXYBATE
Sodium oxybate is also known as gamma-hydroxybutyrate (GHB). An illegal form of GHB—the so-called “date rape drug”—is produced and used illicitly, typically at parties and nightclubs. Some users hide the fast-acting, sedating drug in a cocktail, rendering victims unable to defend against an assault or to recall details leading to the assault.1
Some athletes believe GHB enhances on-field performance by increasing production of growth hormone. Enhanced growth hormone release has no known clinical significance or effect on athletic performance, however.
Sodium oxybate: Fast facts
Drug brand name: Xyrem
Class: CNS depressant
FDA-approved indications: Treatment of cataplexy
Approval date: July 17, 2002
Manufacturer: Orphan Medical
Dosing forms: 180 mL oral solution at a concentration of 0.5 grams/mL
Recommended dosage: Start at 2.25 grams at bedtime; repeat dose overnight (4.5 grams/d total). Dosage can be increased to 9 grams/d (4.5 grams per dose) by increments of 0.75 grams per dose every 2 weeks. A dropper is supplied to facilitate measurement.
The U.S. Drug Enforcement Agency (DEA) considers GHB a Schedule 1 (illegal) drug. DEA considers the prescription version a Schedule 3 drug, meaning it can be prescribed with refills as long as a DEA number is listed on the prescription. To prevent misuse, a central pharmacy dispenses sodium oxybate and mandates use of a specific prescription form to verify the physician’s familiarity with the medication. Psychiatrists can call (866) 997-3688 to obtain the form.
Sodium oxybate dosing recommendations for patients
Sodium oxybate is the only agent FDA-approved for treating cataplexy—muscle weakness common among patients with narcolepsy.
HOW IT WORKS
Developed as an anesthetic, sodium oxybate induces deep sleep and at higher doses causes amnesia.
Derived from gamma-aminobutyric acid (GABA), sodium oxybate’s mechanism of action is unknown. Some believe it binds to the GABA B receptor and partially inhibits the NMDA and AMPA receptor-mediated excitatory neurons in the hippocampus.2
Food alters its bioavailability, so sodium oxybate should be taken several hours after meals to prevent delays in absorption and effect. Patients taking it should not eat at bedtime.
The agent’s pharmacokinetics are nonlinear, meaning that if the dose is doubled, the medication effect is tripled or quadrupled. For this reason, dosage increases must be small (no more than 0.75 grams for each dose) and gradual (at intervals of at least 2 weeks). The medication reaches peak plasma concentration within 30 to 75 minutes, so patients should not take the medication until they are in bed. Its 1-hour half-life explains its brief duration of action and need for repeat dosing overnight (Table 2).
Sodium oxybate does not modify the activity of any cytochrome P-450 enzymes. The medication is high in sodium (0.5 grams in a 3-gram dose) and has a salty taste. Use caution when considering the agent for patients with hypertension or on low-sodium diets.
Sodium oxybate’s safety has not been adequately tested in patients younger than 18 or older than 65 or in those with dementia and other disease processes. Because the drug is metabolized by the liver, the manufacturer recommends prescribing one-half the starting dosage to patients with significant hepatic impairment.
Sodium oxybate has been shown to indirectly reduce frequency of cataplexy by improving nocturnal sleep:
- In a placebo-controlled, 4-week trial, 136 patients received either placebo or sodium oxybate at bedtime and again overnight in two equally divided doses of 3, 6, or 9 grams each. Patients who received the medication experienced less-frequent cataplexy, reduced daytime sleepiness, and fewer unplanned daytime naps and nocturnal awakenings. 3
- A placebo-controlled trial that followed 55 patients for more than 3 years demonstrated long-term efficacy based on the patients’ cataplexy diaries (mean duration of treatment 21 months). Cataplexy returned after abrupt discontinuation. 4
Unlike patients with most other disorders, those with narcolepsy generally are willing to repeat a medication overnight. They awaken easily at night—often without an alarm. Patients taking the medication report that they fall asleep again more readily and experience dramatically improved sleep quality and duration.
Sodium oxybate has been well tolerated in relatively small clinical trials.
In the 4-week, placebo-controlled trial,3 nausea, headache, dizziness, and enuresis were most frequently reported. Out of 136 participants, 1 withdrew because of acute confusion and 9 others left because of mild to moderate adverse events. Twelve others experienced one episode of enuresis—probably because they did not fully awaken from deep sleep when developing urinary urgency. Advise patients taking sodium oxybate to urinate before going to bed.
The medication’s propensity to increase slow-wave sleep may cause sleepwalking. Sleepwalking was reported in 32% of patients in one long-term, uncontrolled study.5 If a patient with a history of sleepwalking needs sodium oxybate, advise against sleeping in upper bunks and other dangerous settings, and recommend precautions such as locking doors.
Because of sodium oxybate’s sedating properties, concomitant use of alcohol, barbiturates, and benzodiazepines should be discouraged.
As discussed, GHB has a high abuse potential with effects such as euphoria, relaxation, and heightened sexual feelings.
Tolerance and dependence has not been reported with sodium oxybate when used as prescribed. A withdrawal state—similar to alcohol and sedative/hypnotic withdrawal and marked by anxiety, tremor, agitation, and delirium—has been reported with GHB abuse (although other chemicals often are used simultaneously in such cases). Narcolepsy patients in clinical trials have abruptly discontinued sodium oxybate after months of use without significant withdrawal.4
- Narcolepsy Network Inc. www.narcolepsynetwork.org
Dr. Krahn reports no financial relationship with Orphan Medical or with manufacturers of competing products.
1. Galloway GP, Frederick SL, Staggers FE, Jr, et al. Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction 1997;92(1):89-96.
2. Cammalleri M, Brancucci A, Berton F, et al. Gamma-hydroxybutyrate reduces GABA(A)-mediated inhibitory postsynaptic potentials in the CA1 region of hippocampus. Neuropsychopharmacology. 2002;27(9):960-9.
3. U.S. Xyrem Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 2002;25(1):42-9.
4. U.S. Xyrem Multi-Center Study Group. The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. J Toxicol Clin Toxicol 2003;41:131-5.
5. Physicians’ Desk Reference (57th ed). Montvale, NJ: Thomson Healthcare, 2003.
6. Mitler MM, Hayduk R. Benefits and risks of pharmacotherapy for narcolepsy. Drug Saf. 2002;25(11):791-809.