Taking Ambien And Xanax: Which To Stop First?

In our latest question and answer, the pharmacist discusses tapering options for those on both a benzodiazepine, like Xanax, and Ambien.

Question

I have been on Xanax 0.5 mg for 4 and 1/2 years, and Ambien 10 mg/day for 15+ years. The Xanax is no longer really helping, but I am sleeping with the zolpidem. In order to get off of these drugs, which should I taper off of first? It is my understanding that both of these meds affect the GABA-A receptors. Some people say to taper the Xanax first, but then others say the zolpidem will impede the recovery of the GABA receptors. I know to taper these medications very slowly and I can do that, I just don't know which to taper first. My doctor is of no help in this and refuses to switch me to a longer-acting benzodiazepine such as diazepam.

Asked by Mar On Jul 05, 2019

Answered by
Medical Content Reviewed By PharmacistAnswers Staff

On Jul 09, 2019
Two Pill Bottles With White Pills Spilling Out

Overview

You are correct that both Ambien (zolpidem) and Xanax (alprazolam) work in a similar manner, and therefore, it can be tricky to find a conclusive recommendation on which to taper first if you are taking both of them.

In fact, there are no definitive guidelines on how to taper either drug, even if you are taking them alone. The fact you are taking them together is an added wrinkle.

Tapering protocols, in general, are highly patient-specific, and have to account for a variety of factors, including:

  • Patient age
  • How long you have been taking the medication to be tapered
  • Concomitant medications
  • Concomitant disease states

In your situation, being on both zolpidem and alprazolam, again, there is no recommendation that states you should taper one before the other. An appropriate tapering protocol could be devised by you and your doctor that involves either medication being discontinued first.

It is incredibly important to work up a tapering protocol with your doctor, as they have your complete medical history and are in the best position to give you guidance.

Nevertheless, if we are following the general medication tapering mantra of 'start low and go slow' (meaning to start your dose reduction from your current dose and incrementally decrease slowly over time), it would make sense to work down on your zolpidem first.

I say this because while zolpidem and alprazolam work on the some of the same receptors (i.e. GABA-A), alprazolam has a wider range of activity. The actions of zolpidem are directed to a smaller number of these receptors (I discuss this in more detail in the next section).

Stopping a medication that has a narrower mechanism of action than the other (assuming they work in a similar manner overall) first makes intuitive sense. It would be like going on a diet and stopping the consumption of a single unhealthy item, like donuts, first, as opposed to stopping all unhealthy food immediately. It's essentially a step-down approach.

Having said the above, there certainly are cases where stopping alprazolam first would make sense too, like if your main concern is that you have trouble sleeping at night.

Studies show that alprazolam (and other benzodiazepines) can significantly affect several stages of deep sleep (e.g. stages 3 and 4) but zolpidem doesn't appear to alter these, at least not to a significant degree.

Therefore, in order to better manage a healthy and consistent sleep schedule, having zolpidem as your sole drug to taper (as opposed to tapering a benzodiazepine like Xanax on top of it) may make it easier to successfully manage and monitor your sleep.

An additional reason to potentially decrease alprazolam first is that benzodiazepines overall are well-documented to be difficult to discontinue and some patients can experience moderate to severe withdrawal symptoms.

Zolpidem, on the other hand, is generally associated with less severe withdrawal symptoms, which occur at a much lower rate than with benzodiazepine withdrawal. In fact, the prescribing information for Ambien states the following:

"...following placebo substitution occurring within 48 hours following last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less."

Since benzodiazepines are more closely associated with difficult withdrawal, taking zolpidem (which works on some of the same receptors as benzodiazepines) during an alprazolam tapering period may decrease the overall incidence and severity of potential withdrawal reactions, although this has not been shown (or tested for that matter) in studies.

All of these considerations are why it is so important to discuss an appropriate tapering protocol with your doctor that matches your specific medical situation so you can be monitored and have adjustments initiated as necessary.


Ambien Vs. Xanax Mechanism Of Action

Ambien Bottle On Stone Table

Xanax (alprazolam) is classified as a 'benzodiazepine', while Ambien (zolpidem) is not, although it is similar. Nevertheless, Ambien, when described in medical literature, is specifically noted as a 'non-benzodiazepine' hypnotic drug.

While I could go into extensive details regarding the differences between how Ambien and Xanax work, the prescribing information for Ambien gives a fairly good description:

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines or other drugs with known hypnotic properties, it interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the (BZ1) receptor preferentially with a high affinity ratio of the alpha1/alpha5 subunits.

To boil this down, it is simply stating that although Ambien (zolpidem) and benzodiazepines (like Xanax) share several pharmacologic properties, Ambien is not considered a benzodiazepine. Additionally, while benzodiazepines interact with all of the 'benzodiazepine receptors' (i.e. BNZ receptors) in the body, Ambien only interacts with a select few.

There are several types of BNZ receptors in the body:

  • BNZ-1 receptors (located in the cerebellum and cerebral cortex)
  • BNZ-2 receptors (located in the cerebral cortex and spinal cord)
  • BNZ-3 receptors (located in peripheral tissues)

Activation of the BNZ-1 receptor, which is what zolpidem acts on, is thought to modulate sleep.

Activation of the other BNZ receptors (e.g. BNZ-2 receptors) has other effects, including:

  • Muscle relaxation
  • Anticonvulsant activity
  • Alterations to motor coordination
  • Anxiolytic activity

As Ambien does not interact with all of the BNZ-receptors that benzodiazepines like alprazolam do, this is thought to be the reason that it does not possess many of the effects associated with benzodiazepines (e.g. muscle relaxation, anxiolytic (e.g. anti-anxiety) and anticonvulsant effects).

Additionally, the lack of zolpidem's activity on BNZ-2 and BNZ-3 receptors is why zolpidem isn't thought to significantly affect stages of deep sleep (e.g. stages 3 and 4) or REM sleep.


Tapering Recommendations

Pill Taper Stock Image

As mentioned previously, there is no single recommendation for tapering medication that applies to everyone. There are, however, some several suggestions and recommendations found in various medical sources.

Xanax Taper

Benzodiazepines can be notoriously difficult to get off of and they are associated with several potential withdrawal reactions, including:

  • Sweating
  • Increased heart rate
  • Muscle cramps
  • Tremor
  • Insomnia
  • Anxiety
  • Agitation
  • Nausea
  • Vomiting
  • Hallucinations
  • Seizures

Xanax, in particular, can be more difficult than other benzodiazepines to discontinue since it has a short duration of action, which generally means that withdrawal symptoms can occur more rapidly.

An example of a general tapering recommendation for benzodiazepines is as follows:

  • Decrease your dose by 25% in the first week, and 25% the second week. From there, decrease by about 10% every week and adjust accordingly based on withdrawal symptoms.

Tapering generally takes at least a few weeks, but can also extend for months based on whether or not you are experiencing any withdrawal symptoms.

For short-acting benzos, like alprazolam, taper durations are generally on the longer end.

For what it is worth, the prescribing information for Xanax offers the following recommendation as it concerns tapering to avoid withdrawal reactions:

To discontinue treatment in patients taking XANAX, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of XANAX be decreased by no more than 0.5 mg every three days. Some patients may benefit from an even slower dosage reduction.

In practice, this recommendation (to decrease by no more than 0.5mg every three days) may be too aggressive for some. A slower titration is generally recommended, especially if you have been on the drug for a long time or have been taking a high dose.

Zolpidem Taper

The prescribing information for Ambien doesn't necessarily recommend tapering the drug if you are looking to discontinue it. Nevertheless, the abrupt discontinuation of the drug has been associated with several withdrawal reactions, including:

  • Dysphoria
  • Muscle cramps
  • Rebound insomnia
  • Sweating
  • Tremors
  • Convulsions

Interestingly enough, the Canadian prescribing information for zolpidem does recommend tapering the drug for certain individuals:

...abrupt discontinuation should be avoided and a gradual dosage-tapering schedule is recommended for patients taking the drug for more than a few weeks.

Tapering protocol recommendations vary, but you could certainly follow guidelines for benzodiazepines, which involve decreasing your dose by a certain percentage (e.g. 25%) every week or so.


Final Words

Unfortunately, as discussed in this answer, there is no definitive recommendation on which drug to discontinue first, Ambien or Xanax, if you are taking both of them.

Xanax has been more strongly associated with withdrawal effects and being on Ambien may help to somewhat mitigate them since they act on some of the same receptors. This hasn't been tested clinically, however.

Additionally, benzodiazepines like Xanax can affect certain stages of sleep (e.g. stage 3, 4 and REM sleep) while Ambien doesn't appear to. Stopping Xanax first, then Ambien, may be a good way to evaluate how your sleep is affected by these drugs.

On the other hand, since Xanax has a broader spectrum of action, it may make sense to discontinue zolpidem first if you rely on the anxiolytic or anticonvulsant effects of the drug. This would also represent a more gradual taper approach.

In any case, you should discuss with your doctor the best approach for your medical situation.


Summary

Ambien (zolpidem) and Xanax (alprazolam) have similar pharmacologic actions, but the overall effect and receptor interaction of Xanax is more wide-ranging. There is currently no recommendation regarding which to taper first if you are taking both of them. There are many factors to consider and you should discuss a tapering protocol with your doctor that best suits your situation.

References
  1. Xanax Monograph. AccessFDA
  2. Ivadal Monograph. Sanofi-aventis
  3. Ambien Monograph. AccessFDA
  4. Alprazolam Monograph. NIH Bookshelf
  5. Detoxification from high-dose zolpidem using diazepam. PubMed
  6. Deprescribing benzodiazepine receptor agonists. PubMed
  7. Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research. PubMed
  8. Management of benzodiazepine misuse and dependence. PubMed

About the Pharmacist

Dr. Brian Staiger Pharm.D

Dr. Brian Staiger is a licensed pharmacist in New York State and the founder of PharmacistAnswers.com. He graduated from the University At Buffalo with a Doctor of Pharmacy degree in 2010. He has been featured in numerous publications including the Huffington Post as well as a variety of health and pharmacy-related blogs. Please feel free to reach out to him directly if you have any inquiries or want to connect! He's answered thousands of medication and pharmacy-related questions and he's ready to answer yours! Brian.Staiger@PharmacistAnswers.com Office: 716-389-3076

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