A 28 y/o male patients has been diagnosed with narcolepsy after a long work-up several years ago. His symptoms at that time included excessive daytime somnolence, cataplexy, hallucinations at sleep onset, and muscle paralysis upon awakening.  He was treated with various central nervous system (CNS) stimulants. They all seemed to work initially but after time their therapeutic effect lessened requiring a switch to different drugs.

In a recent journal article a colleague read about a new drug therapy approved for narcolepsy, sodium oxybate. Since this drug can be easily abused, you're a little bit apprehensive.

Do you order the sodium oxybate or not? Why or why not?

SELECT  here for discussion

**THANKS to MAJ (Dr.) Libby Schindler for all her help with this Pearl.**
** This was a real case.**

Narcolepsy is a disorder featuring the inability to maintain daytime wakefulness AND disorder of REM (rapid eye movement) sleep regulation. According to Harrison's textbook of medicine (15th edition), there is a narcolepsy "tetrad" which includes the following:

-    Excessive daytime sleepiness/somnolence PLUS three specific symptoms related to intrusion of REM sleep to include:

o    sudden weakness or loss of muscle tone, without loss of consciousness, often elicited by emotion (cataplexy)

o    hallucinations at sleep onset (hypnogogic hallucinations) or upon awakening (hypnonopompic hallucinations)

o    muscular paralysis upon awakening (sleep paralysis) The DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders) diagnostic criteria for Narcolepsy are: 

A.    Irresistible attacks of refreshing sleep that occur daily over at least 3 months

B.    The presence of at least one or both of the following:

       1.    Cataplexy (i.e. brief episodes of sudden bilateral loss of muscle tone, most often in association with intense emotion)

       2.    Recurrent intrusions of elements of rapid eye movement 9REM) sleep into the transition between sleep and wakefulness, as manifested by either hypnopompic or hypnogogic hallucinations or sleep paralysis at the beginning or end of sleep episodes

C.    The disturbance is not due to the direct physiologic effects of a substance (e.g, a drug of abuse, a medication) or another general medical condition.

The extent and duration of attacks can vary. They can be short lived with minimal symptoms or, in rare cases, as long as 20-30 minutes with total body flaccid paralysis. Symptoms usually starts in a patient's 20s but can occur anytime between 5 and 50 years of age. There does seem to be a genetic basis for this disorder in some cases.  Most patients describe years of attacks prior to seeking clinical attention.

Treatment is symptomatic and usually starts with CNS stimulants. Methylphenidate [Ritalin®] is usually the drug of first choice. Starting dose is 2.5 - 5.0 mg two times a day and increasing as necessary to 20mg po four times a day. Pemoline [Cylert®] has and can be used but I would discourage people from using it because of the paperwork involved/required after it's reports of fatal hepatic failure. Dextroamphetamine [Dexedrine®] has also been used. Modafanil [Provigil®] has been evaluated and carries an FDA approval for the treatment of excessive daytime somnolence in narcolepsy. Its unique mechanism of action, once daily dosing and fewer reported side effects make it an attractive drug therapy choice.

Other REM sleep suppressive agents can be used to treat the cataplexy, hypnogogic hallucinations and sleep paralysis and include the tricyclic agents protriptyline and clomipramine and the SSRI, fluoxetine.

When these agents fail or lose their therapeutic effect, one can consider sodium oxybate for these patients. This agent is unique since it carries bifurcated DEA schedule. Gamma-hydroxybutyrate  [aka GHB, grievous bodily harm, liquid ecstasy, Georgia Home Boy, etc.] was classified as a Schedule I controlled substance (no recognized medical use) in 2000.  The same chemical entity under the name sodium oxybate [Xyrem®] was approved as a DEA schedule III controlled substance in the 4th quarter of 2002. An easy way to remember it is - if you get it via prescription it's a schedule III, if you buy on the street from 'some dude', it's a schedule I.

Lots of info on sodium oxybate from MICROmedex is condensed and listed below. Sodium oxybate is a hypnotic. I know you're asking WHY would we give hypnotics to narcoleptic patients who can't stay awake in the first place? It's kinda like giving stimulants to hyperactive kids. The hypothesis suggest by improving a narcoleptic patient's nighttime sleep they're less likely to experience the daytime somnolence and less of the other CNS and somatic manifestations of narcolepsy.

Abuse potential - especially in patients with alcohol or opiate dependence or addiction. Remember, the DEA categorizes controlled substances based on their abuse potential. For example, a schedule II controlled substance has demonstrated, in the opinion of the DEA, a greater abuse potential than a schedule IV controlled substance. From MICROmedex:

0.0 OVERVIEW

A. Sodium oxybate (gamma hydroxybutyrate) is a naturally occurring inhibitory neurotransmitter with hypnotic-anesthetic properties.

B. DOSING INFORMATION: For adults with cataplexy associated with narcolepsy, the recommended starting dose is 4.5 grams/day orally in 2 equal doses of 2.25 g, the first taken at bedtime while in bed and the second 2.5 to 4 hours later. The dose may be increased to a maximum of 9 g/day in two-weekly increments of 1.5 g/day. Oral doses of 50 to 100 milligrams (mg)/kilogram (kg) daily have been used for alcohol withdrawal and insomnia; intravenous doses of 50 mg/kg have been used in general anesthesia; for anesthesia in pediatric patients, 100 mg/kg orally or 50 mg/kg intravenously have been used for anesthesia.

C. PHARMACOKINETICS: Sodium oxybate gastrointestinal absorption is rapid, with peak serum concentrations reached within 25 to 60 minutes (min) after oral administration, and 15 min after intravenous infusion; oral bioavailability is 25%; no plasma protein binding is observed and the elimination half-life varies widely from 23 to 56 min. Sodium oxybate is metabolized by alcohol dehydrogenase or by beta-oxidation, completely oxidized via the Krebs' cycle, and eliminated via the lungs as carbon dioxide; renal excretion of unmetabolized sodium oxybate is less than 1%.

D. CAUTIONS: Adverse effects, reversible with discontinuation of treatment, include confusion, headache, nausea, vomiting, dizziness and urinary incontinence. Sodium oxybate is contraindicated in patients being treated with sedative hypnotic agents and in patients with succinic semialdehyde dehydrogenase deficiency.

E. CLINICAL APPLICATIONS: Sodium oxybate is indicated for the treatment of cataplexy in patients with narcolepsy and, as a Schedule III controlled substance, is available through the Xyrem Success Program(SM) (1-866-997-3688). It is under investigation as a general anesthetic (general surgery, cardiac surgery and cardiac catheterization, in obstetrics for labor and delivery, for mechanical ventilation in status asthmaticus), as sleep cover in epidural anesthesia, for alcoholism and opiate withdrawal, for reduction of cerebral edema due to head trauma, in fibromyalgia syndrome, and for treatment of insomnia and obstructive sleep apnea.

1.3.1 NORMAL DOSE

     A. IMPORTANT NOTES

        1. In the United States, sodium oxybate is available on through restricted distribution, the Xyrem Success Program(TM), by calling 1-866-XYREM88(1-866-997- 3688).

        2. Sodium oxybate contributes 0.5 gram of sodium per 3-gram dose. This should be considered in patients with heart failure, hypertension, or compromised renal function (Prod Info Xyrem(R), 2002).

        3. Avoid abrupt withdrawal after high-dose long-term treatment. Abrupt withdrawal can lead to a withdrawal syndrome similar to ethanol withdrawal and includes risk of delirium tremens.  Sodium oxybate withdrawal should be managed the same as ethanol withdrawal.

     B. ORAL NARCOLEPSY

        1. The recommended starting dose of sodium oxybate for treatment of cataplexy in patients with narcolepsy is 4.5 grams/day: 2.25 grams at bedtime, while in bed, and a second dose 2.5 to 4 hours later. The dose may then be increased to a maximum of 9 grams/day in increments of 1.5 grams/day (0.75 grams per dose) at intervals of 2 weeks. Effective doses are 6 to 9 grams/day (Prod Info Xyrem(R), 2002). D

DOSAGE IN HEPATIC INSUFFICIENCY

A. In patients with hepatic dysfunction, the starting dose should be reduced by half, and dose increments should be closely monitored (Prod Info Xyrem(R), 2002).

B. Significant modification of the sodium oxybate pharmacokinetic profile is observed in liver cirrhosis; in particular, increased mean plasma levels. The recommended dose is 25 to 50 milligrams/kilogram/day (Ferrara et al, 1996).

ONSET AND DURATION

2.1.1 ONSET

A. INITIAL RESPONSE:

Sedation, oral: 15 to 45 minutes (Lammers et al, 1993; Scrima et al, 1989; Scharf et al, 1985; Lansade et al, 1985; Broughton & Mamelak, 1980; Broughton & Mamelak, 1979)

2.1.2 DURATION ABSORPTION

     A. BIOAVAILABILITY (F):

         1. Oral, solution: 25% (Prod Info Xyrem(R), 2002).

         2. After oral administration, plasma levels of sodium oxybate increase more than proportionally with increasing dose (3.7-fold with doubling of dose from 4.5 to 9 grams) [AKA non-liner kinetics] (Prod Xyrem(R), 2002).

2.3.2.1 DISTRIBUTION SITES

     A. TOTAL PROTEIN BINDING: less than 1% (Prod Info Xyrem(R), 2002; Palatini et al, 1993)

        1. In 8 healthy volunteers, sodium oxybate did not bind to plasma protein (Palatini et al, 1993).

     B. VOLUME OF DISTRIBUTION (Vd): 0.19 to 0.58 L/kg (Prod Info Xyrem(R), 2002; Palatini et al, 1993; Dyer, 1991)

        1. In 8 healthy volunteers, sodium oxybate volume of distribution was 0.33 L/kg after a 25 mg/kg oral dose (Palatini et al, 1993). A two-compartment model with volume of distribution of 0.4 L/kg (first compartment) and 0.58 L/kg (second compartment) was observed after intravenous administration (Dyer, 1991). In 16 cirrhotic patients, the volume of distribution was 0.24 L/kg (Ferrara et al, 1996).

2.3.3 METABOLISM

2.3.3.1 METABOLISM SITES AND KINETICS

Liver, extensive (Prod Info Alcover(R), 1999) Sodium oxybate is metabolized by alcohol dehydrogenase to succinic acid (Hoes et al, 1978; Doherty et al, 1975; Vree et al, 1975) in a capacity-limited process (Palatini et al, 1993) or by beta-oxidation with subsequent metabolism to carbon dioxide in the Krebs' cycle (Vickers, 1969). The primary site of metabolism of sodium oxybate is the liver (Prod Info Alcover(R), 1999).

2.3.4 EXCRETION

2.3.4.1 BREAST MILK

     A. BREASTFEEDING: Unknown

        1. The manufacturer recommends caution when administering sodium oxybate to a pregnant woman, as no data are available on breast milk excretion (Prod Info Xyrem(R), 2002).

2.3.4.2 KIDNEY

     A. RENAL CLEARANCE: 0.07 mL/kg/min (Palatini et al, 1993; Ferrara et al, 1992)

     B. RENAL EXCRETION: 1% to 5% (Palatini et al, 1993; Ferrara et al, 1992; Dyer, 1991)

     C. In 8 healthy volunteers (Palatini et al, 1993) and in 10 alcoholic patients treated with oral sodium oxybate 25 mg/kg, renal excretion was less than 1% (Ferrara et al, 1992). Higher renal excretion values (2% to 5%) were observed after intravenous administration (Dyer, 1991).

     D. OTHER EXCRETION:

        1. FECES, neglible (Prod Info Xyrem(R), 2002)

        2. EXPIRATION, most (Prod Info Xyrem(R), 2002)

2.3.5 HALF-LIFE

2.3.5.1 PARENT COMPOUND

     A. ELIMINATION HALF-LIFE: 20 to 53 minutes (Scharf et al, 1998; Ferrara et al, 1996; Palatini et al, 1993; Ferrara et al, 1992) A non-linear elimination (similar to ethanol and phenytoin) has been shown in humans (Palatini et al, 1993; Ferrara et al, 1992).

3.0 CAUTIONS

3.1 CONTRAINDICATIONS

A. Current treatment with sedative hypnotics
B. Succinic semialdehyde dehydrogenase deficiency

3.2 PRECAUTIONS

A. Compromised respiratory function
B. Hepatic insufficiency
C. History of depression
D. Hypertension or heart failure (high sodium dose with sodium oxybate)
E. Simultaneous ingestion of alcohol and other central nervous system depressant drugs
F. Alcohol or opiate abuse (potential for sodium oxybate abuse)

PLACE IN THERAPY

Sodium oxybate is indicated for the treatment of cataplexy in patients with narcolepsy (Prod Info Xyrem(R), 2002).

Studies have shown sodium oxybate to be useful in the treatment of narcolepsy, fibromyalgia syndrome, and insomnia, as well as for increase in slow wave sleep (SWS, stages 3 and 4) and REM efficiency, and decrease in SWS latency and stage 1 duration.

Alcoholism and opiate withdrawal may be treated effectively with sodium oxybate in acute or chronic stages, but its abuse potential is a risk in alcohol- and opiate-dependent patients.

A. MECHANISM OF ACTION

     1. Sodium oxybate (gamma hydroxybutyrate) is a naturally occurring inhibitory neurotransmitter with highest concentration in the basal ganglia, which mediates sleep cycles, temperature regulation, cerebral glucose metabolism and blood flow, memory, and emotion control. It is formed from the precursor molecules gamma-butyrolactone (GBL, the lactone form of sodium oxybate), 1,4-butanediol, or 4-hydroxycrotonic acid and is metabolized to succinic semialdehyde, then to succinic acid (via the Krebs' cycle) or to gamma-aminobutyric acid (GABA) (controversial) (Li et al, 1998; Tunnicliff, 1997; Feigenbaum & Howard, 1996; Cash, 1994; Escuret, 1991; Vickers, 1969; Mitoma & Neubauer, 1968).

     2. Sodium oxybate binds to gamma aminobutyric acid (GABA)-B receptors and sodium oxybate specific receptors. At low doses, it causes a reduction in dopaminergic activity in the basal ganglia (possibly due to the inhibition of dopamine-releasing nerve cells) and, at high doses, it can stimulate dopamine release; it also interacts with serotonin, opiates, and cholinergic pathways, and the effects are also dependent on several undefined variables (Tunnicliff, 1997; Li et al, 1998; Martellotta et al, 1997; Feigenbaum & Howard, 1996; Cash, 1994). In an animal model of myoclonus induced by intraperitoneal injection of the GABA-agonist muscimol, the effect was reduced by sodium oxybate in a manner similar to baclofen (Menon, 1981).

     3. Sodium oxybate may produce anesthesia by a general suppressant action on the entire cerebrospinal axis, and muscular relaxation by an action on the spinal cord rather than a direct action on the neuromuscular junction (Doherty et al, 1975). The anesthetic effect does not correlate with brain concentration (Vickers, 1969). Sodium oxybate markedly inhibits the H-reflex responses in normal and narcoleptic subjects, but no effect was observed on F-response, suggesting a presynaptic inhibition in the spinal cord (Mamelak & Sowden, 1983). Polysomnographic recorders in healthy patients showed significant increases in slow wave sleep (SWS, stages 3 and 4) and REM efficiency, and decreases in SWS latency and stage 1 sleep after sodium oxybate treatment (Lapierre et al, 1990).

     4. Electroencephalographic changes observed in humans (adult and childhood) during general anesthesia with sodium oxybate showed a slow delta-theta or only delta rhythm, with alpha and beta power decreasing and delta increasing. No seizure-like electrical activity was observed, in contrast to previous animal studies (Li et al, 1998; Entholzner et al, 1995; Ducloux et al, 1989; Vickers, 1969; Metcalf et al, 1966). Visual evoked potentials showed a reduction of amplitude and latency time after sodium oxybate infusion (Jimenez et al, 1982; Desbordes et al, 1982).

     5. In multiple studies, sodium oxybate has reduced tissue oxygenation demands and protected cells during an hypoxic state. These effects have been demonstrated in animal models of hemorrhagic shock, coronary artery occlusion, stroke, hepatic ischemia, and fetal hypoxia (Li et al, 1998). Protective effects on liver and lungs during long-term, hypothermic organ storage were reported in animal studies (Yamasaki et al, 1996; Sherman et al, 1994).

6. In several studies, sodium oxybate has significantly increased growth hormone (GH) release, prolactin secretion, and cortisol secretion, but no effect was observed on thyrotropin (TSH) and melatonin levels (Van Cauter et al, 1997; Gerra et al, 1995; Gerra et al, 1994; Takahara et al, 1977). GH release induced by sodium oxybate was antagonized by flumazenil and metergoline, but not by naloxone pretreatment (Gerra et al, 1995; Gerra et al, 1994), thus involving an effect on gamma-aminobutyric acid (GABA) and serotonergic systems. In alcoholic patients after 1 to 2 years of abstinence, sodium oxybate (and also sumatriptan, a serotonergic 5-HT1D agonist) failed to increase GH release (Vescovi & Coiro, 1997). In parkinsonian patients, sodium oxybate increased GH release, but other GABA-ergic agents (baclofen and sodium valproate) did not, suggesting that the stimulatory effect of sodium oxybate is not mediated by a GABA-ergic pathway (Volpi et al, 1997).

NARCOLEPSY ASSOCIATED CATAPLEXY FDA Labeled Indication

1. OVERVIEW:
         FDA APPROVAL: Adult, yes; pediatric, no
         EFFICACY: Adult, effective
         DOCUMENTATION: Adult, good

2. SUMMARY:
          - Sodium oxybate significantly reduces cataplexy attacks and daytime sleepiness
            in patients with narcolepsy
          - Sodium oxybate is an effective treatment for narcolepsy, with significant reductions in cataplexy and sleep attacks, and improvement in polysomnographic readings
          - In United States, available only through Xyrem Success Program(SM) (1-866-997-3688)

3. ADULT:

     a. Sodium oxybate reduced the number of cataplexy attacks and reduced daytime sleepiness in patients with narcolepsy. After discontinuation of hypnotic drugs and medications used to treat cataplexy, 136 patients underwent a washout period of at least 5 half-lives of the discontinued anticataplexy medication before being randomly assigned, in a double-blind manner, to sodium oxybate 3, 6, or 9 grams (g), or placebo, administered in equal divided doses at bedtime and 2.5 to 4 hours later, for 4 weeks. At baseline, the weekly frequency of cataplexy attacks ranged from 3 to 249 (median 21). The one patient with 249 attacks per week (who was receiving the 6-g dose) had an aberrant response to sodium oxybate, with an increase in attacks over the 4-week study. Excluding his data from analysis, the weekly frequency of cataplexy decreased significantly with the 6-g and 9-g doses when compared to placebo (p=0.0327 and p=0.0008, respectively). Daytime sleepiness, as assessed by Epworth Sleepiness Scale (ESS) improved in all groups in a dose-related manner, reaching significance (p=0.0001) in the 9-g dose group when compared to placebo. There were significant decreases in the number of inadvertent naps/sleep attacks at both the 6-g and 9-g doses (p=0.0497 and p=0.0122, respectively) and in nocturnal awakenings at the 9-g dose (p=0.0035). The most common adverse events were nausea, vomiting, dizziness, and enuresis. Most adverse events occurred early in the study and decreased over time. One patient experienced a serious adverse event in the form of an acute confusional state. During the 3- to 5- day washout period at the end of the trial, the number of cataplexy attacks increased in each treatment group (Anon, 2002). In an extension of this study, 118 patients took sodium oxybate 3, 4.5, 6, 7.5, or 9 grams nightly, on the same schedule as in the 4-week study (Anon, 2003). Cataplexy attacks/week continued to decrease by an average of 24 (p less than 0.001) at 1 month and, at the end of the study period (12-months), by an average of 35. (This is a mean decrease of 90% or more from experience before the 4-week trial.) Overall improvement in daytime sleepiness was maximal after 2 months (p less than 0.001) and significant at all doses, with an approximately 30% decrease in Epworth Sleepiness Scale from the pre-treatment mean. That response was maintained throughout the study. The most common adverse events were headache, nausea, viral infection, dizziness, pain, enuresis, and somnolence.

     b. Oral sodium oxybate (30 milligrams/kilogram (mg/kg) before nighttime sleep and 30 mg/kg 4 hours later) for 4 weeks was effective for narcolepsy in a randomized, placebo-controlled, double-blind, crossover study with 24 patients (13 males and 11 females, mean age 36 years). Sodium oxybate significantly reduced hypnagogic hallucinations, daytime sleep attacks and subjective daytime sleepiness in comparison to placebo. Patient global assessment was significantly in favor of sodium oxybate (p less than 0.001) (Lammers et al, 1993).

     c. In a randomized, placebo-controlled, double-blind, crossover study of 20 patients (10 males and 10 females, mean age 47.5 years) with narcolepsy disorder, 28-day sodium oxybate treatment (oral 25 milligrams/kilogram (mg/kg) at bedtime and again 3 hours later) significantly reduced cataplectic events (p = 0.022 versus placebo; in particular during the third and fourth week), hypnagogic hallucinations (p = 0.008) and arousals (p = 0.035). No difference between active and placebo treatments was observed on sleep attacks, Stanford Sleepiness Scale ratings at morning wakening, methylphenidate usage, and daytime naps. Placebo treatment was also significantly effective in comparison to baseline in reducing cataplectic events in the first 2 weeks and the number of sleep attacks. Fewer adverse effects were observed with sodium oxybate (nausea, dizziness, urinary urgency, fatigue) than placebo (Scrima et al, 1989). Polysomnographic recordings of nocturnal sleep showed a significant difference in favor of sodium oxybate versus placebo in reducing stage 1 time and awakenings, increasing stage 3 and delta sleep (stages 3 and 4), and sleep depth and continuity (Scrima et al, 1990).

     d. In a case series with 16 narcoleptic patients (8 males and 8 females, mean age 41.8 years) with cataplexy attacks, sodium oxybate 50 milligrams/kilogram in 2 oral doses at night improved the quality of sleep and reduced the major symptoms of narcolepsy and cataplexy. Muscle weakness, abdominal pain, arm dysesthesias, urinary urgency, and (rarely) a dream-like confusional state were the adverse effects noted, with 2 dropouts (Broughton & Mamelak, 1979). Polysomnographic recordings of nocturnal sleep showed reductions in stage 1 time (from 73.8 to 47.8 min, p less than 0.005) and rapid eye movement (REM) latency (from 66.7 to 16.9 min, p less than 0.005), and increases in stages 3 and 4 times and sleep efficacy. Daytime recordings showed significant decreases in total sleep time, stages 3 and 4 and REM times (Broughton & Mamelak, 1980). Similar results were observed in another study with 30 narcoleptic patients (13 men and 17 women, mean age 45.7 years) treated with sodium oxybate in a total oral dosage of 5 to 7 grams for 30 weeks (Scharf et al, 1985).

This Pearl is meant for academic and educational purposes only. This Pearl is meant to raise important points regarding the safe and cost-effective pharmacotherapy of patients. It is not meant to be the definitive reference for the treatment or prophylaxis of various diseases. Although every effort is taken to ensure this Pearl is correct and factual, errors may occur. The US Air Force, the 59th Medical Wing (MDW), and 59th MDW Pharmacy assume no liability for incorrect information or harm that may occur from the use of the information included in this Pearl.