Z-drugs, otherwise known as benzodiazepine receptor agonists, are used to help patients with insomnia that is associated with difficulty falling asleep (sleep latency), difficulty staying asleep (sleep maintenance), or not feeling rested after a night’s sleep (sleep quality). While there aren’t a ton of differences, understanding sleep onset and subtle pharmacokinetic differences can help us best manage our patients’ medications. We’ve outlined some of those differences in our Z-drug comparison chart later in this article.
It is important to understand that these medications are recommended for short-term use in patients for the treatment of insomnia AFTER trying non-pharmacologic options like cognitive behavioral therapy or practicing good sleep hygiene. They have the potential to exhibit similar side effects as benzodiazepines such as dizziness, excessive sedation, and postural instability. Some of these medications are responsible for next-day sedation and can cause something we call complex sleep behaviors that manifest as sleep eating, sleep walking, and even sleep driving in 1-5% of patients. The problem with these behaviors is it is a risk to not only the patients themselves but others as well. Patients many times will not have any recollection of this happening and discontinuation of therapy will be required.
This class of medications is also on the BEERS list published by the American Geriatrics Society (AGS). Increased sedation and drowsiness in this patient population can lead to an increased risk of falls. When older adults experience falls it is harder for them to recover and can increase their overall risk for mortality. This population is especially vulnerable to the side effects of z-drugs even though these medications are being prescribed quite often. Insomnia prevalence in older adults is leading to an increase in medications prescribed. It is important that we are aware these medications are on the BEERs list and older adults are at increased risk for falls and/or complex sleep behaviors. It may be difficult to discontinue these medications due to the sleep troubles they may be experiencing, but taking extra precautions and observation is especially necessary when elderly patients are prescribed z-drugs.
Z-Drug (Benzodiazepine Receptor Agonist) Reference Chart for Sleep Onset or Maintenance
Generic (Brand) | Dose Range | Onset (min) | Enzymatic Breakdown | Elimination Half-life (hrs) | Sleep Onset, Maintenance or Both | Clinical Pearls |
| Eszopiclone (Lunesta) | 1-3mg(All patients should start with 1mg) | 30-60 | CYP3A4 (major) CYP2E1 (minor) | 5-6 | Both | Take without food Dose-dependent metallic taste Duration=5-12 hours |
| Zolpidem IR (Ambien) | 5-10mg(Start with 5mg in women*) | 30-90 | CYP3A4 | 1.4-4.5 | Onset | Rebound insomnia not associated with zolpidem IR Take without food Duration=1-5 hours |
| Zolpidem CR (Ambien CR) | 6.25-12.5mg(Start with 6.25mg in women*) | 30-120 | CYP3A4 | 1.62-4.05 | Both | Take without food No clear advantage of CR zolpidem vs IR zolpidem except for duration Duration=5-12 hours |
| Zolpidem SL (Edluar) | 5-10mg(Start with 5mg in women*) | 30-180 | CYP3A4 | 1.57-6.73→5mg1.75-3.77→10mg | Onset | Dissolve under the tongue Take without food Duration=5-12 hours |
| Zolpidem SL (Intermezzo) | 3.5mg-Male1.75mg-Female | 35-75 | CYP3A4 | 1.4-3.6 | Middle of the night awakenings | Take only if there is ≥4 hours before wake time Dissolve under the tongue Take without food Duration=1-5 hours |
| Zolpidem OS (Zolpimist) | 5-10mg(Start with 5mg in women*) | 10-50 | CYP3A4 | 1.7-5→5mg1.7-8.4→10mg | Onset | Take without food Duration=1-5 hours |
| Zaleplon (Sonata) | 5-20mg | 30-60 | Aldehyde Oxidase (Major) CYP3A4 (Minor) | 1 | Onset | Dose-dependent rebound insomnia Take without food Duration=1-5 hours |
As displayed in the Z-drug comparison table above, these medications have delayed onset if taken with or immediately following a meal. It is important to counsel patients about this especially if sleep latency is a significant problem. We do not want to have them take a medication designed to help them fall asleep faster, but have that onset delayed by taking it with food.
Z-Drug Comparison – Drug-Drug Interactions:
Z-drugs are all metabolized by the liver enzyme CYP3A4 to some extent whether it is the major or minor pathway that brings with it drug interactions that we must be aware of. A few medications that are potent inhibitors of this enzyme are clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, and verapamil. When taken simultaneously, the z-drug concentration is increased leading to further risk for adverse events and unwanted side effects. There are also a few medications that are responsible for CYP3A4 induction leading to decreased z-drug concentration and sub-therapeutic response like phenobarbital, phenytoin, rifampicin, St. John’s Wort, and glucocorticoids.
Zaleplon is the only z-drug where CYP3A4 is not the major pathway in its metabolism. It does get metabolized by this enzyme to some extent and can be affected by the above medications, but it is primarily broken down by aldehyde oxidase to its inactive form prior to excretion. Cimetidine is a medication that comes to mind when talking about aldehyde oxidase inhibition. This medication can expectedly cause an increase in zaleplon concentrations and risk for adverse effects.
While comparing z-drugs and knowing the specific pharmacokinetic differences between them can be important, it is crucial to remember that geriatric patients are increasingly susceptible to the adverse effects and use should be avoided if possible. Hopefully, our Z-drug comparison chart helps you remember some of these differences!
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Article written by Jeff Mueller, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCGP, BCPS
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References:
Product Information: Edluar(R) oral sublingual tablets, zolpidem tartrate oral sublingual tablets. Meda Pharmaceuticals Inc. (per FDA), Somerset, NJ, 2013.
Product Information: AMBIEN(R) oral tablets, zolpidem tartrate oral tablets. sanofi-aventis US LLC (per FDA), Bridgewater, NJ, 2022.
Product Information: AMBIEN CR(R) oral extended-release tablets, zolpidem tartrate oral extended-release tablets. sanofi-aventis U.S. LLC (per FDA), Bridgewater, NJ, 2016.
Product Information: Intermezzo(R) sublingual tablets, zolpidem tartrate sublingual tablets. Purdue Pharma L.P. (per FDA), Stamford, CT, 2015.
Sherwood DA, Morin AK. Sleep disorders. In: Zeind CS, Carvalho MG, Eds. Applied Therapeutics: The Clinical Use of Drugs. 11th ed. Philadelphia, PA: Wolters Kluwer Health, 2018: 1762-79.
Clinical Resource, Comparison of Insomnia Treatments. Pharmacist’s Letter/Prescriber’s Letter. June 2022. [380603]
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