A recent study in Psychiatry Research confirmed alprazolam (Xanax) was associated with an increased risk of suicide. Two other benzos, diazepam (Valium) and lorazepam (Ativan) were also associated with an increased risk of suicide. “The increased risk extends to benzodiazepines in general, regardless of half-life and risk of withdrawal seizure.” However, buspirone (BuSpar), a non-benzodiazepine anxiety-reducing medication showed significantly less risk of suicidality.
Mad in America reported the study estimated continued use of alprazolam was associated with 2.21 times increased risk of suicide events compared to non-use. When cases of overdose were excluded, the risk of suicide events was still more than double (2.10). However, when individuals without a psychiatric diagnosis used alprazolam, their risk of suicide tripled (3.04). And these individuals also tended to take other psychiatric drugs with alprazolam.
44.9% of participants were taking antidepressants along with alprazolam. 15.43% were taking muscle relaxants, and 10.89% were taking a drug to help with insomnia. Other medications taken alongside alprazolam in the current work include ADHD drugs (6.27%), antipsychotics (4.26%), mood stabilizers (2.25%), gabapentinoids (5.99%), alcohol use disorder drugs (0.10%), opioid use disorder drugs (0.81%), non-benzodiazepine anxiety drugs (5.82%), antiepileptics (4.22%), and tobacco cessation drugs (1.26%).
The researchers examined data from 2,495,520 individuals. The data used in the study was collected between 2010 and 2020. Participants were followed for up to two years. Most were male (69.66%). The most common diagnosis, when there was a diagnosis, was anxiety disorder (43.85%), followed by depression (19.93%). They concluded:
Our findings indicate that suicidality should be closely monitored in patients prescribed benzodiazepines in general, both short-acting and long-acting, and that alternative non-benzodiazepine anxiolytic medications be considered for the treatment of anxiety in suicidal patients.
Addiction and Withdrawal Concerns with Benzos, Especially Alprazolam
These concerns with suicidality, as well as with addiction or physical dependence are not really new concerns; they have been known about benzodiazepines for a while. Beginning in September of 2020 the FDA finally required the boxed warnings for all benzodiazepine medications be updated to note the risk of abuse, physical dependence and withdrawal reactions. The FDA thought the 2020 prescribing information did not provide adequate warnings about the serious risks and harms associated with these medications. So, the existing Medication Guides were also required to update their information. The FDA said:
We reviewed post-marketing databases, adverse event cases reported to FDA, and the published literature. Our review found that benzodiazepines are widely prescribed and widely abused and misused in the U.S., often for long periods of time. Also, some patients have had serious withdrawal reactions after benzodiazepines were stopped suddenly or the dose was reduced too quickly. Some patients experienced withdrawal symptoms lasting many months.
The Lancet published a comparative summary of clinical guidance on the prescriptive guidelines for benzodiazepines (BZD) and so-called “Z-Drugs” (BZRA) like Ambien for anxiety disorders, mood disorders and insomnia. The study also gave guidance for deprescribing and discontinuing BZD and BZRA. Their results indicated a general lack of specific prescription guidance for BZD in major depression and associated mood disorders other than to limit the concurrent use of a BZD to less than than 4 weeks with an antidepressant. “There were few guidelines that made clear recommendations for management of BZD in patients with concomitant mood and anxiety disorders.”
When BZD are used for anxiety related disorders, there is a clear consensus among most documents to restrict their use to the ‘short-term’ (often unspecified in terms of duration) but most commonly for less than 4 weeks. Interestingly, alprazolam which has become noticeably more problematic in terms of misuse or harm based on real world data over the past two decades, is still over-represented as a BZD of choice in many guidance documents.
In particular, alprazolam garnered attention as both a cure and curse for many people. It was the ninth most prescribed psychiatric medication in 2020, according to PsychCentral. Clonazepam (Klonopin) and lorazepam (Ativan) also made it into the top 20 most prescribed medications for 2020. There was a Netflix documentary, Take Your Pills: Xanax, made by Maria Shriver and her daughter Christina Schwarzenegger. Their film looked at how people wanted a quick fix for their anxiety. “With Xanax, you feel the impact right away.”
Alprazolam (Xanax) and diazepam (Valium) were also found by the CDC to be among the top ten drugs involved in unintentional drug overdose deaths from 2011 through 2016. Alprazolam was ranked fifth with 5,510 deaths (10.1%) and diazepam was ranked tenth with 1,723 deaths (3.1%). For overdose deaths involving suicide, alprazolam ranked fourth with 468 deaths (9.2%). Alprazolam was also mentioned in 26% of the overdose deaths involving hydrocodone, 22% of the deaths involving methadone, and 25% of the deaths involving oxycodone. See “Xanax Is Not the Way Out of Anxiety.”
The Lancet researchers said real world evidence of harm via overdose and diversion trends should be considered in framing future recommendations when prescribing a BZD. They noted how newer studies advise against using alprazolam, given its rapid onset and shorter half-life, which increase its potential for withdrawal and misuse. Another area of divergence in prescriptive guidance was with dosing. Some guidelines suggest regular scheduled dosing of BZD for anxiety disorders, while others advise ‘prn’ use or intermittent dosing.
How prescriptions are issued and used in real world medical practice can have profound effects on the development of tolerance or dependence for individuals with these conditions and so this is an area where further clarity could be achieved within future guidelines. This is especially important because recent observational research indicates potentially safer outcomes with intermittent compared to chronic dosing.
Deprescribing and the Ashton Manual
The area of deprescribing was barely investigated and often patient-driven. Heather Ashton first wrote about “The treatment of benzodiazepine dependence” in 1994. She said the benzodiazepine dosage should be tapered at an individually titrated rate, typically under the patient’s control. She advised that psychological support be available during dose reduction and for some months after the cessation of the drug. The support should include information about benzodiazepines, general encouragement, “and measures to reduce anxiety and promote the learning of non-pharmacological ways of coping with stress.”
With these methods, success rates of withdrawal are high and are unaffected by duration of usage, dosage or type of benzodiazepine, rate of withdrawal, symptom severity, psychiatric history or personality disorder. Longer-term outcome is less clear; a considerable proportion of patients may temporarily take benzodiazepines again and some need other psychotropic medication. However, the outcome may be improved by careful pharmacological and psychological handling of withdrawal and post-withdrawal phases.
Heather Ashton eventually wrote and made available her work on benzodiazepine tapering in The Ashton Manual for free. She provided information on what the drugs do in the body; how to withdraw after long-term use; and suggested slow withdrawal schedules. The Lancet researchers noted where the Ashton Manual was not included in their review because of it was a single-authored document and it explicitly stated the information was for the use of the general public as opposed to healthcare providers. The Ashton Manual said: “The material published in this online Manual is for general health information to the public. The author and publisher are not engaged in rendering medical, health, psychological advice or any other kind of personal or professional services on this site.”
The researchers hoped that the shifting of BZD deprescribing practices from a clinical ‘art’ to a clinical ‘science’ should be a continued focus for guideline committees, with attention to dose reduction, the use of longer-acting BZDs, and other deprescribing practices. For more information on the concerns with benzodiazepines, see “Are Benzos Worth It?” and “It Takes Away Your Soul.”
