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Xyrem & Xywav

Updated: Nov 20, 2021

Here's a new mnemonic mascot for Xywav, which is a newer formulation of oxybate (Xyrem). As a preface we will look at narcolepsy and orexin. The mechanism of oxybate (GHB) does not involve orexin but includes a visual mnemonic of a narcolepsy sufferer, which includes the mnemonic for orexin.


Orexin

Orexin was discovered in 1998 almost simultaneously by two independent groups of researchers, one group naming it orexin and the other hypocretin. The name orexin derives from the Greek word orexis, meaning “appetite” (also part of the word anorexia). Orexin stimulates appetite (anorexia involves lack of appetite). Orexin also promotes wakefulness. The hypo- in hypocretin refers to the hypothalamus, where orexin-producing neurons reside.

Orexin (hypocretin) by Dr Jason Cafer MD - Oreo mnemonic
Orexin mascot
Sleep-wake cycle with orexin by Dr Jason Cafer MD

Narcolepsy

Narcolepsy (with cataplexy) is a condition of orexin deficiency. Narcolepsy is caused by autoimmune destruction of orexin-producing cells in the hypothalamus. The Greek derivative of the word narcolepsy means “to be seized by sleep”. The disorder is characterized by recurrent periods of an irrepressible need to sleep. The disorder typically includes episodes of cataplexy, not to be confused with catalepsy (muscular rigidity and fixity of posture), which is not a feature of narcolepsy.


Cataplexy is a brief (seconds to minutes) episode of sudden loss of muscle tone, often precipitated by strong emotions. A patient may report “my knees sometimes buckle when I laugh”. A person experiencing cataplexy stays awake and aware of what is happening, but cannot move for about a minute. They may fall asleep afterward.


Narcolepsy cataplexy by Dr Jason Cafer MD - cat plexiglass oreo

The mechanism of cataplexy relates to the natural loss of muscle tone associated with rapid eye movement (REM) sleep. This natural paralysis is necessary to keep you from acting out your dreams and falling out of bed. With cataplexy, the paralysis of REM sleep occurs while the individual is awake.


When sleeping, individuals with narcolepsy/cataplexy may enter REM sleep quickly, for instance within 15 minutes rather than 90 minutes. Narcoleptic/cataplexic individuals may also experience sleep paralysis while falling asleep or awakening, remaining conscious but unable to move or speak. Sleep paralysis may be accompanied by hypnagogic or hypnopompic hallucinations. Hypnagogic refers to “going to sleep”. Hypnopompic refers to the period of “pomping up” from sleep before being fully awake. These hallucinations may be auditory, visual, or tactile. Before being understood, sleep paralysis was called the “sleep hag” or “old hag” phenomenon, during which a person feels a presence of a supernatural malevolent being immobilizing them, e.g., by sitting on their chest.


Cataplexy, sleep paralysis and hypnagogic/hypnopompic hallucinations all involve going into a REM-like state too easily, caused by orexin deficiency.


Individuals with typical narcolepsy/cataplexy tend to eat less. This is as expected, since orexin is known to stimulate appetite. Despite eating less, these individuals tend to be overweight. This is because orexin is needed for development of brown fat, which (unlike white fat) burns calories.


Medications approved for narcolepsy

The first five are stimulants with similar mechanism involving dopamine (DA) and norepinephrine (NE). Pitolisant has a novel stimulating mechanism. Sodium oxybate is a strong sedative that will be featured below.


► Methylphenidate (RITALIN) - DA > NE reuptake inhibitor (DNRI); Schedule II

► Amphetamine (ADDERALL) - DNRI plus DA > NE releaser; Schedule II

► Modafinil (PROVIGIL) - DA reuptake inhibitor (DRI); Schedule IV

► Armodafinil (NUVIGIL) - DRI; Schedule IV

► Solriamfetol (SUNOSI) - DNRI; Schedule IV

► Pitolisant (WAKIX) - Histamine-3 (H3) antagonist (stimulating); Non-controlled

Sodium oxybate (XYREM) - GHB, CNS Depressant, GABA analogue; Sched III

Calcium, magnesium, potassium, and sodium oxybates (XYWAV) - same as XYREM but 92% less sodium


Orexin Receptor Antagonists

These medications are approved for insomnia. They may cause narcolepsy-like effects and are contraindicated for individuals with narcolepsy.

► Suvorexant (BELSOMRA) - 2015

► Lemborexant (DAYVIGO) - 2020


Sodium Oxybate (XYREM)

FDA-approved for:

Narcolepsy, more specifically “cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy ages seven and older"


Sodium oxybate (Xyrem) is a central nervous system (CNS) depressant approved in 2002 as a Schedule III controlled substance for narcolepsy with cataplexy. It is present endogenously in small amounts, and acts upon GABA(B) receptors and GHB receptors. XyremX’s out REMsleep, so that a greater percentage of the night is spent in deep sleep.


Sodium oxybate is the isolated sodium salt of gamma-hydroxybutyrate (GHB). Only two years earlier (2000) street GHB was outlawed as a Schedule I (illegal) drug by the Date-Rape Prevention Act. Clinical trials of sodium oxybate were already underway when GHB became widely recognized as something that can be slipped into a victim’s drink. In combination with alcohol, GHB can knock a victim unconscious, for about an hour, to awaken with no memory of what transpired.

Sodium Oxybate XYWAV by Dr Jason Cafer MD
Xyrem mascot

Xyrem is only available as a liquid. Street GHB is also a liquid, but can be available in powder, liquid, or pill forms. Street GHB is used as a club drug, known as “liquid ecstasy”, Georgia Home Boy, or just “G”. The club drug can produce an intoxicating euphoria, described as a combination of ecstasy and strong alcohol—a Good Hard Beverage indeed. Euphoria kicks in quickly and lasts about an hour. Unlike other club drugs, there is no significant hangover (that’s Good). GHB is not considered physically addictive, but there may be psychological withdrawal described as a “feeling of doom”.


Using “G” as a club drug is dangerous because a few extra drops and the user is knocked out (Hard). Recreational users should be warned to never mix it with alcohol, and never consume it in a party situation without someone to keep close watch. Partiers have written "G'" on their hands to alert others what happened in the event they lose consciousness. Abuse of GHB (or prescription Xyrem) may lead to respiratory depression, seizures, and coma. Mixing GHB with alcohol may be fatal, but most individuals who overdose on GHB recover completely.


Illegal GHB can be manufactured in the kitchen from a type of paint stripper (GBL). There is no need for a lab setup like what is required for cooking methamphetamine.


OK, back to the legal prescription form of GHB, sodium oxybate. It “repairs” and consolidates sleep, so less time is spent in REM and more time in deep sleep. XyremX’s out REM“ sleep is a useful mnemonic, which also functions as a spelling cue—it starts with X, not Z. A patient reported “When I wake up, I feel completely refreshed; in comparison to the other drugs that are supposed to be ‘clean,’ G really is clean”, which is very Good.


Xyrem is taken as an oral solution diluted by the patient with water using a syringe (Beverage).

Xyrem from Cafer's Psychopharmacology

Xyrem reduces the frequency of cataplexy attacks by about 50%, and the improvement is immediate (that’s very Good). Improvement in excessive daytime somnolence may take a couple of months. Side effects may include nausea (19%), headache (18%), and dizziness (18%). There are no kinetic interactions, as its main route of elimination is by conversion to carbon dioxide. Xyrem has black box warnings for CNS depression and abuse/misuse. To reiterate, do not combine with alcohol or other sedatives.


The patient is instructed to take the 1st dose while in bed and set an alarm to take the 2nd dose 2.5 to 4 hours later. Half-life is only 30–60 minutes. The label recommends not to drive within 6 hours of taking Xyrem. It is primarily excreted by the lungs as CO2 and in the urine.


Xyrem has been found to be as effective as modafinil (Provigil, wakefulness promoting agent) for the excessive daytime sleepiness of narcolepsy. The combination of Xyrem and modafinil is better for narcolepsy than either medication taken alone. Sodium oxybate is very expensive, but the patent is set to expire in 2020.


Now back to illegal GHB. It has been used by bodybuilders because it increases secretion of growth hormone during sleep. It has a short half-life, and by 24 hours it will not be detectable by a urine drug test. In case you wondered, GHB is not the “Roofie” date rape drug—that would be the benzo Rohypnol (flunitrazepam).

Xyrem interactions (bubble) by Dr Jason Cafer MD

Dosing:

Give at least 2 hours after food. Start 2.25 grams in bed at HS, repeat 2.25 grams when the alarm sounds 2.5 to 4 hours later (total starting dose 4.5 grams, divided). Increase by 1.5 grams/day (divided 0.75 grams/dose) q week to target of 6–9 grams (divided 3–4.5 grams/dose). Max is 9 grams (divided 4.5 grams/dose). The most common maintenance doses are 6 g, 7.5 g, and 9 g.


Calcium, magnesium, potassium, and sodium oxybates

(XYWAV)

Here's the new content.

Xywav (sodium oxybates, GHB) by Dr Jason Cafer MD
Xywav mascot

Sodium oxybate (Xyrem) released in 2002, contains a lot of salt. At the target dose of 6–9 grams the patient consumes 1,092–1,638 mg of sodium nightly. By perspective, total dietary salt intake should not exceed 1,500–2,000 mg daily.


Xywav, the new formulation of this medication, contains 92% less sodium than Xyrem by including other cations— calcium, magnesium, and potassium.

Xyrem vs Xywav what's the difference / comparison

Otherwise Xyrem and Xywav are identical. The active component is GHB. Dosing is the same. They are both approved to treat narcolepsy, more specifically “cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy ages seven and older”. They are both Schedule III controlled substances.


Xywav GHB interaction mnemonic by Dr Jason Cafer MD - bubble

Dosing: Same as with Xyrem


More high yield mnemonics can be found in Cafer's Psychopharmacology, Visualize to Memorize 270 Medication Mascots.






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