Are doxepin, zolpidem (Ambien), and eszopiclone (Lunesta) associated with addiction?

From the Guidelines

Yes, doxepin, zolpidem, and eszopiclone can all be addictive, though their addiction potential varies. Zolpidem (Ambien) and eszopiclone (Lunesta) have higher addiction potential as they are both sedative-hypnotics in the "Z-drug" class that work similarly to benzodiazepines by enhancing GABA activity in the brain. These medications can cause physical and psychological dependence, especially when taken at higher doses or for longer than recommended (typically no more than 2-4 weeks) 1. Doxepin, primarily used as an antidepressant but also available in low doses (Silenor) for insomnia, has lower addiction potential but can still cause dependence with long-term use. All three medications may lead to withdrawal symptoms if stopped abruptly after regular use. For this reason, these medications should be used at the lowest effective dose for the shortest duration possible, and discontinuation should involve gradual tapering under medical supervision. Non-medication approaches to managing insomnia, such as cognitive behavioral therapy for insomnia (CBT-I), should be considered before or alongside these medications.

Some key points to consider:

• The U.S. Food and Drug Administration has released safety announcements on the risk for serious injuries caused by sleep behaviors associated with nonbenzodiazepine BZRAs, such as zolpidem and eszopiclone 1.
• Low-dose doxepin has no black box warning for suicide risk, but the risk for suicidal ideation associated with use of low-dose doxepin as a hypnotic agent is unknown and cannot be excluded 1.
• The work group advised against use of benzodiazepines or trazodone for treatment of chronic insomnia disorder due to the widely known harms and adverse effects of these medications 1.
• Cognitive behavioral therapy for insomnia (CBT-I) is a non-pharmacologic behavioral intervention that is more effective than pharmacologic therapies for treatment of chronic insomnia disorder and has lesser concerns about harms 1.

The most recent and highest quality study recommends that nonbenzodiazepine BZRAs, such as zolpidem and eszopiclone, should be administered at the lowest effective dose and for the shortest possible duration, and all patients offered these agents should be counseled on the potential risks 1.

From the FDA Drug Label

Doxepin is virtually devoid of euphoria as a side effect Characteristic of this type of compound, Doxepin has not been demonstrated to produce the physical tolerance or psychological dependence associated with addictive compounds.

• Doxepin: The FDA drug label states that doxepin is not associated with addiction, as it does not produce physical tolerance or psychological dependence.
• Zolpidem (Ambien) and Eszopiclone (Lunesta): The FDA drug label does not provide information about these medications. The FDA drug label does not answer the question about zolpidem and eszopiclone.

From the Research

Association with Addiction

• Doxepin, zolpidem (Ambien), and eszopiclone (Lunesta) are associated with some risk of dependence and abuse, although concerns regarding such risks appear to be greater than warranted by empirical evidence 2.
• The non-benzodiazepines, including zolpidem and eszopiclone, are associated with some risk for dependence and abuse, but the appropriate therapeutic use of hypnotics is generally not associated with physiological responses that are commonly thought to lead to dependence, such as tolerance or discontinuation effects 2.
• Former substance abusers and psychiatric patients appear to be at greatest risk of dependence and abuse 2.
• Benzodiazepines, which are sometimes used to treat insomnia, have a high abuse potential 3.

Comparative Risks

• Zolpidem and eszopiclone were more efficacious than placebo for acute treatment of insomnia, but were also associated with a higher number of dropouts due to adverse events 4.
• Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo, and zopiclone caused more dropouts than did eszopiclone 4.
• Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions 4.

Safety Profiles

• The non-benzodiazepine hypnotics, including zolpidem and eszopiclone, are generally well tolerated and present favorable safety profiles in comparison with the older benzodiazepines and barbiturates 2.
• Commonly cited impairments of memory formation and decrements in psychomotor performance are related to the mechanism of action of hypnotics, and are both dose- and time-dependent 2.
• The labelling of hypnotics was recently updated to incorporate warnings about very rare, but serious adverse events, including anaphylaxis, angio-oedema, and complex sleep-related behaviors 2.