The study found no significant cognitive impairment in adults with long-term use of BZD 20. A study of over 2000 older adults assessed the effects of chronic BZD use on cognition 21. Chronic use of BZD leads to a small but significant change in fluid intelligence, while long-term use of BZD correlates with worse cognitive decline when compared to the effects of using a high dosage 21.
Characteristics of misuse among younger and older adults
- These findings illustrate that gender differences in misuse might vary according to prescription status and age.
- We aimed to obtain data on the prevalence of benzodiazepines abuse and poisoning in older adults; the prevalence of polypharmacy with benzodiazepines in this demographic; and investigate whether abuse and poisoning occurred more frequently with benzodiazepine hypnotics or benzodiazepine anxiolytics.
- Analyses of 2008–2014 NSDUH data found that adults with OUD had a rate of combined sedative/tranquilizer misuse that was approximately 20 times greater than the U.S. general population, with 43% reporting past-year sedative/tranquilizer misuse (Votaw et al., 2019).
- Agarwal and Landon 2019 stated that the prescription of BZD in outpatient settings significantly increased from 2003 to 2015 27.
- The dependence on BZDs generally leads to withdrawal symptoms, which necessitates careful tapering of the medication when prescribed 26.
Conversely, there are reports of withdrawal from carbamazepine and clonidine with symptoms similar to those seen in alprazolam withdrawal, including psychosis (Adler et al., 1982; Heh et al., 1988) and hyperadrenergic states (Tollefson, 1981). Carbamazepine is metabolized by CYP3A4, and interactions with other drugs that induce, inhibit, or compete for CYP3A4 are relatively common, which may limit its use. Clonidine acts exclusively at the alpha-2 adrenoceptors levels and lacks carbamazepine’s GABAergic function and mood stabilization, thus leaving patients to experience all the other withdrawal symptoms if used alone for detoxification.
Withdrawal
We defined those with past-year benzodiazepine use disorders as individuals who misused benzodiazepine-only tranquilizers in the past year and had prescription tranquilizer use disorders or who misused benzodiazepine-only sedatives in the past year and had prescription sedative use disorders. Benzodiazepine abuse is common in those on methadone maintenance treatment (MMT), so special consideration must be taken for those withdrawing from the drugs while on MMT 68. These patients are more likely to die from methadone toxicity because of the synergistic effects of methadone and BZD 68.
The review found that the onset of the anxiolytic effect was significantly more rapid for alprazolam compared with amitriptyline, and its antipanic effect was significantly more rapid compared with propranolol and imipramine. Alprazolam has been consistently found to approximate the magnitude of anxiolytic effect of other comparable benzodiazepines. Due to the lack of nationally representative data, it has not been possible to date to estimate what proportion of users meet criteria for misuse or use disorders and which users are at greatest risk for benzodiazepine misuse or use disorders. Participants reported an average of nearly 17 years of regular benzodiazepine use (i.e., at least 3 days a week), often without consistent follow-up visits to health care settings where emerging signs of addiction might have noted. Many started with as-needed (pro re nata or PRN) prescriptions and initially thought they “did something good” (P11) by taking the drugs.
Second, some CIs around the strong associations with other substance use disorders are wide, which indicate limited precision of the estimates. Third, among past-year adult benzodiazepine misusers in the U.S., we estimated the main motivations for the most recent misuse and assessed the source of benzodiazepines obtained for the most recent misuse stratified by the status of benzodiazepine use disorders. This study used SUDAAN software24 to account for the complex sample design and sample weights of NSDUH. Perceptions of communication and experiences of changes to prescribing over time were the shared, organizing concepts in the themes 27 that resulted from our reflexive thematic analysis of open-ended questions about benzodiazepine initiation and long-term use. A potential limitation is that the interview guide did not include specific questions about patient-prescriber interactions or changes in prescribing over time.
- The suppression of CaMKIIa by diazepam has a long-lasting effect leading to a limited neuronal response to changes in intracellular calcium and decreased response by GABA-A receptors 42.
- The ultimate concern is that such fetuses will later be susceptible to autism, learning difficulties, attention deficit disorder, and general hyperactivity 24.
- Future studies separating these different forms of misuse are also needed to determine their relative clinical significance.
Table 2.
Notwithstanding these risks, it is surprising that research investigating how benzodiazepines, such as alprazolam, interact with opioids is severely lacking in clinical and preclinical settings. This review therefore aims to present our current knowledge of benzodiazepine use and misuse, with an emphasis on alprazolam when data is available, and particularly in populations at higher risk for developing substance use disorders. Additionally, the potential mechanism(s) surrounding tolerance, dependence and abuse liability are discussed. Despite their popularity, our understanding of how benzodiazepines and opioids interact is less than adequate. Therefore, it is now more important than ever to understand the short- and long-term consequences of benzodiazepine/alprazolam use. The COVID-19 pandemic has caused a disruption of the availability of critical mental health services and as a result many people may have faced an increase in the use of alcohol and drugs 1.
4. Long-Term Effects of Benzodiazepine Use
Pregnant women and fetuses are at increased risk for adverse effects of withdrawal; they both metabolize BZD slowly, and the drug can cross the placenta to cause concentrations to build up to significant levels in the neonate 18. While a therapeutic dose has not been proven teratogenic, use during pregnancy has been linked to low birth weight, preterm labor, and intrauterine growth restriction. The unborn fetus is at high risk for “floppy infant syndrome,” characterized by muscle laxity, failure to suckle, and oversedation. Approximately two weeks after birth, the infant experiences withdrawal consisting of continued difficulty feeding, high pitched cries, hyperexcitability, and consequently possible failure to thrive. The ultimate concern is that such fetuses will later be susceptible to autism, learning difficulties, attention deficit disorder, and general hyperactivity 24. A study analyzing over 1000 cases of oxycodone-related drug abuse deaths showed that BZDs are among the most abused drugs by individuals using multiple drugs of abuse.
Alcohol is involved in 1 in 4 ED visits resulting from BZD abuse and is involved in 1 in 5 BZD-related deaths.18 Both alcohol and BZDs bind to distinct binding sites on the GABAA receptor, ultimately leading benzodiazepine use, misuse, and abuse: a review to synergistic drug actions. In addition, health care professionals should make necessary interventions and referrals when problematic alcohol consumption is suspected or identified. We performed a brief systematic literature review concentrating on instances of benzodiazepine poisoning and abuse among older adults diagnosed with insomnia.
NSDUH is cross-sectional and, due to the 2015 redesign, we cannot track trends in misuse over time. NSDUH response rates have been declining, though this is unfortunately true for several federally-administered national surveys (47). NSDUH is nationally-representative, but of the civilian population and therefore does not include active-duty members of the military or institutionalized adults. We included past-year alcohol, marijuana, and heroin use or abuse/dependence; past-year use of tobacco products; and past-year prescription use, misuse, or abuse/dependence of prescription opioids and stimulants. NSDUH was redesigned in 2015 to collect more detailed information on the use and misuse of prescription medications, including benzodiazepines—in prior years, questions were limited to misuse exclusively (25). The pre-2015 NSDUH definition of misuse was limited to “nonmedical use”, but the 2015 definition was revised to include “in any way a doctor did not direct.” This analysis is limited to the 2015 and 2016 survey years, the years available post-redesign.
Alprazolam should not be prescribed at a higher dose than is US FDA-recommended, and providers should consider discontinuation if patients are requesting higher doses, as it may signal therapeutic tolerance and/or misuse. Since the 1970s, research has found negative effects of BZD on recipients’ cognitive functions (7). A meta-analysis in 2017 investigated the long-term cognitive impacts of BZD among adults. This analysis reported impairments in working memory, language, and processing speed, but not in executive function (reasoning and planning) (8). Compared to young adults, elderly populations require more cautiousness when undertaking BZD therapy.
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