Xyrem Bottles

Intro

Xyrem (sodium oxybate) is an interesting drug choice for the treatment of narcolepsy in that it is quite unlike other, and more commonly used, therapeutic options, like amphetamines.

Sodium oxybate is neither an amphetamine nor is it a stimulant. In fact, it is a CNS (central nervous system) depressant and has more in common with benzodiazepines than it does drugs like Adderall.

You may have read that Xyrem contains the active ingredient GHB, colloquially known as the 'date-rape drug', and that is true.

GHB stands for 'gamma-Hydroxybutyric acid' (or γ-Hydroxybutyric acid) and sodium oxybate is a simply the sodium salt form of γ-Hydroxybutyric acid.

To clarify this, it helps to point out that, in general, drugs have three distinct names, a chemical name, a non-proprietary pharmaceutical name (e.g. 'generic name') and a brand, or proprietary name.

Take Lipitor for example, a very popular 'statin' drug:

  • Chemical name: [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1Hpyrrole-1-heptanoic acid
  • Generic name: Atorvastatin
  • Brand name: Lipitor

For Xyrem:

  • Chemical name: Sodium gamma-hydroxybutyrate
  • Generic name: Sodium oxybate
  • Brand name: Xyrem

Making GHB a sodium salt doesn't change the overall effects of the drug, but allows for improved stability and ease of manufacturing in a liquid solution.

Since Xyrem is a CNS depressant, you may be wondering how it is beneficial for a disorder (narcolepsy in this case) that is associated with excessive daytime sleepiness and falling asleep suddenly.

I discuss this in the next section.


How Xyrem Works

It isn't precisely known what causes a person to suffer from narcolepsy and we don't have a full understanding of the physiology behind it. Nevertheless, several contributing factors are thought to be:

  • Low levels of hypocretin (also known as orexin), a neurotransmitter in the brain that helps control sleep and wake cycles.
  • Disease, infection or injury that alters hormone levels or causes injury to areas of the brain that control sleep.

We know specifically that the amount of REM (rapid eye movement) sleep you get plays a major role in narcolepsy, and measuring it (via sleep studies for example) is a diagnostic indicator.

The REM stage of sleep is a 'deep' sleep and is thought to be necessary for retaining memories and overall functional learning. Having the appropriate amount of REM sleep is also strongly related to next-day wakefulness. Many studies show that a decrease in REM sleep is linked to grogginess and daytime sleepiness.

The major benefit of Xyrem is thought to be that it induces REM sleep. However, the drug may work by additional mechanisms we don't completely understand. This is evidenced by the brief description of the 'mechanism of action' found in the FDA-approved prescribing for the drug:

Xyrem is a CNS depressant. The mechanism of action of Xyrem in the treatment of narcolepsy is unknown.

Even though there is still much to learn about Xyrem, multiple studies have shown that it affects dopamine release as well and, as mentioned above, induces REM sleep. It may also increase delta sleep, which is associated with a state of 'deep-sleep'.

Regardless of its exact mechanism, studies for the drug show that it is effective in many different areas relating to narcolepsy, including decreasing excessive daytime sleepiness and increasing wakefulness. In fact, one particular trial reported that over 60% of individuals taking 9 grams of Xyrem per day reported 'much improved' or 'Very Much Improved' scores on an 'impression of change' scale.

As an additional point, it is important to mention that Xyrem is also used for the treatment of cataplexy, a disorder characterized by a near complete loss of voluntary muscle tone brought on by strong emotions like laughing or crying. Studies show that Xyrem decrease in the total number of weekly cataplexy episodes of nearly 70% has been reported in clinical trials in adult patients receiving a dose of 9 grams per night.


How To Take Xyrem

The dosing recommendations for Xyrem are presumably quite unlike any other drug you have taken.

It is recommended to be taken before bedtime, with another dose to be given 2.5 to 4 hours after that initial dose. This means you will need to wake up to re-dose.

The prescribing information gives the following guidance in regard to dosing:

  • Prepare both doses of Xyrem prior to bedtime.
  • Prior to ingestion, each dose of Xyrem should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy containers provided.
  • Patients should take both doses of Xyrem while in bed and lie down immediately after dosing as Xyrem may cause them to fall asleep abruptly without first feeling drowsy.

It is important to note that most patients that take Xyrem will also be prescribed additional medication to manage their narcolepsy symptoms. The most commonly used adjunct medications are amphetamines (like Adderall), Provigil and Nuvigil.


Final Words

To sum everything up, Xyrem is a unique therapy for the treatment of narcolepsy and is not a stimulant drug (although it is often prescribed along with them). While the exact mechanism of action isn't known, it likely exerts its effects mainly by improving REM sleep.

One point I didn't touch on is the fact that you cannot simply get a prescription for Xyrem and bring it to your local pharmacy.

Xyrem is only available through a REMS (Risk Evaluation and Mitigation Strategies) program, which are established to ensure the benefits of the drug outweigh the potential risks. Both the prescriber and pharmacy need to be certified to prescribe/dispense the product.

Additionally, patients also need to register in the program to receive Xyrem.

Summary

  • Xyrem (sodium oxybate) is approved for the treatment of narcolepsy and cataplexy.
  • The mechanism of action isn't completely understood, but its effects on REM sleep likely are responsible for patients reporting improved wakefulness scores.
  • Xyrem is the sodium salt of GHB and is only available via a REMS (Risk Evaluation and Mitigation Strategies) program.

  • References
    1. Xyrem Prescribing Information. Jazz
    2. Illicit gamma-hydroxybutyrate (GHB) and pharmaceutical sodium oxybate (Xyrem®): differences in characteristics and misuse. PubMed
    3. Atorvastatin Monograph. PubChem
    4. Gamma-hydroxybutyrate (GHB): a scoping review of pharmacology, toxicology, motives for use, and user groups .PubChem
    5. Xyrem REMS. Xyrem