Ambien vs. Xyrem for primary insomnia
An early MetaMed draft research report comparing two sleep drugs — zolpidem (Ambien), the standard prescription hypnotic, and sodium oxybate (Xyrem), an anesthetic-class drug with high recreational abuse potential best known as the date-rape drug GHB but also approved for narcolepsy and studied off-label for sleep architecture. The audience is a clinician deciding first-line therapy for an otherwise healthy insomnia patient.
Comparison of Ambien and Xyrem for use in primary insomnia Ambien (zolpidem) has been used in the treatment of primary insomnia in multiple large clinical trials since 1993, and has proven to be effective, non-habit forming and well tolerated for this purpose. Xyrem (also known as gamma hydroxybutyrate or sodium oxybate) has been restricted due to its recreational abuse potential, and its efficacy in the treatment of insomnia has never been examined in a large clinical study. Most data on the use of Xryem has been collected in the treatment of narcolepsy and fibromyalgia, where it has proven effective in improving symptoms of these disorders and improving daytime wakefulness. While there exists some evidence that Xyrem might improve sleep quality by increasing the percentage of slow wave sleep (SWS), the preponderance of evidence of Ambien’s efficacy in increasing total sleep time, decreasing latency to sleep, and improving self-reported well being make it the favored first-line therapy for insomnia.
Ambien has a moderate half-life of 2.5 hours and can be used for both the induction and maintenance of sleep in the treatment of insomnia. A 10 mg dose increases total sleep time on the order of 1–2 hours/night and decreases latency to sleep on the order of 10–30 minutes reliably in most clinical trials.
1 The number of subjective awakenings per night is also decreased by approximately 1 per night with. More importantly, functional outcomes such as subjective sleep satisfaction and work performance are improved using rating scales such as the 24 point Epworth Sleepiness scale and the Work Limitations Questionairre.
2 Thus not only does the use of Ambien for insomnia increase the total amount of sleep, but users feel more rested and alert the next day.
Ambien does not appear to alter sleep architecture, leaving the percent of time spent in REM sleep unchanged and the percent of time spent in slow wave (deep) sleep either unchanged or slightly elevated.
3,4 No significant tolerance or rebound insomnia after withdrawal have been reported above baseline at therapeutic doses of Ambien. Moreover, it can be taken on an as needed basis without sacrificing efficacy, allowing patients to decide their own dosing schedules.
5 While Ambien is not currently recommended for long-term use, a clinical trial of patients taking Ambien for 12 months showed no increased tolerance or rebound insomnia above baseline.
6 Ambien extended release has been approved for long-term use in insomnia.
The most common side effects associated with Ambien are drowsiness, headache, and dizziness, and a garden variety of other CNS disturbances have been recorded including amnesia, confusion, hallucinations, and mood disturbances. When compared with placebo, no significant psychomotor, cognitive, or memory impairment are observable 7 hours after dosage.
4 Ambien exacerbates the effects of sleep apnea and is not recommended for use in apneics.
4 Xyrem has never been approved for use in insomnia, so most data comes from its use in the treatment of narcolepsy and fibromyalgia. From a practical perspective, Xyrem has a very short half life of 30–60 minutes, and is thus prescribed in twice nightly doses. This makes it less desirable for patients who have trouble staying asleep as opposed to falling asleep, and is partially responsible for the drug’s increased abuse potential. Meta analysis of the multiple clinical trials using Xyrem in the treatment of narcolepsy show that Xyrem use does not significantly decrease sleep latency time or increase total sleep time.
7 It does significantly increase the percentage of time spent in slow wave (deep) sleep, which is from where its benefits are thought to derive. Narcoleptics taking Xyrem showed improved daytime wakefulness, decreased cataplexy attacks, and decreased sleep attacks.
8 Since fibromyalgia patients were found to have decreased slow wave sleep, Xyrem was tested as a treatment for these patients, and found to have similar benefits. While latency to sleep and total sleep time were unchanged, time spent in slow wave sleep was increased and day time wakefulness and vitality questionnaire scores were improved. Xyrem has recently been used in a clinical trial with patients with Parkinson’s disease and again found to increase time spent in slow wave sleep and improve daytime wakefulness in this population.
9 It is tempting to theorize that Xyrem might improve daytime wakefulness in general by increasing time spent in slow wave sleep without increasing total sleep time, but data in a non-diseased population are sorely lacking. Given the consistency of its effects in three different disease populations, it is likely that healthy individuals could experience similar benefits to the quality of their sleep and restfulness, though the effect sized would likely be smaller.
While Xyrem is considered to have a high abuse potential, tolerance and dependence were not seen to develop in patients at the doses used in clinical trials (2.5–9 grams/night). The most common side effects are nausea, headache, dizziness, drowsiness, and urinary disorders (including incontinence and urinary retention). In a 2 year study of long-term use of Xyrem in narcoleptics, no severe adverse events were reported, and none of the minor adverse events caused patients to stop taking Xyrem.
10 It should be noted that this population was already using Xryem for > 7 months to qualify for enrollment, so anyone with immediate large adverse reactions would have self-selected out. Xyrem is a CNS depressant and exacerbates sleep apnea, leading to increased oxygen desaturation and potentially respiratory arrest and death.
11 It is not recommended for use in sleep apneics.
Ambien has proven safe and effective in the treatment of primary insomnia on a variety metrics, including decreasing sleep latency time, increasing total sleep time, and improving daytime wakefulness. While Xyrem has been shown to improve daytime wakefulness, the populations it was tested in had known sleep architecture disorders, making it difficult to assess its usefulness in primary insomnia. Ambien is thus the obvious choice for the treatment of simple primary insomnia. Xyrem holds potential benefits for patients with known reductions in slow wave sleep.
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