Next Article in Journal
Evaluating Public Behavior toward Antibiotic Use in Riyadh: A Cross-Sectional Study
Previous Article in Journal
Multi-Faceted Approach to Ventricular Tachycardia: A Review of Management Strategies
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmacoepidemiology
Volume 3
Issue 3
10.3390/pharma3030019
pharmacoepidemiology-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Benzodiazepine Adverse Reaction Cases Age 50 and Older Reported to the U.S. Poison Centers: Healthcare Use and Major Medical Effects

by
Bryan Y. Choi
1,*,
Namkee G. Choi
2,
C. Nathan Marti
2 and
S. David Baker
3
1
Department of Emergency Medicine, Philadelphia College of Osteopathic Medicine, Bayhealth Medical Center, Dover, DE 19901, USA
2
Steve Hicks School of Social Work, The University of Texas at Austin, Austin, TX 78712, USA
3
Central Texas Poison Center, Temple, TX 76508, USA
*
Author to whom correspondence should be addressed.
Pharmacoepidemiology 2024, 3(3), 285-296; https://doi.org/10.3390/pharma3030019
Submission received: 7 August 2024 / Revised: 26 August 2024 / Accepted: 29 August 2024 / Published: 31 August 2024
Versions Notes

Abstract

:
Background: Despite widespread consensus on the need to reduce benzodiazepine (BZD) use in older adults, prescription rates in the U.S. have paradoxically increased over the past few decades. Objective: We examined (1) the characteristics of the BZD adverse reaction cases in patients aged 50 and older that were admitted to a healthcare facility (HCF) and experienced major effects/death, and (2) the associations between the concomitant use of opioids and/or antidepressants and HCF admission and major effects/death among BZD cases. Methods: We used the 2015–2022 National Poison Data System (NPDS), which contained data from 55 America’s Poison Centers. We fitted two multivariable logistic regression models to examine the associations between the co-use of opioids and/or antidepressants and HCF admission and major effects/death. Results: Of the BZD cases that were examined (N = 1979), 14.9% or 295 cases were admitted to healthcare facilities, and 8.5% of those who were followed up (77 out of 893 cases) experienced major effects or death. The number of co-used substances, co-use of opioids and antidepressants, atypical antipsychotics, anticonvulsants, muscle relaxants, and Gabapentin were associated with greater odds of healthcare admission. Co-use of opioids and healthcare admission were associated with greater odds of major effects/death. Conclusions: Adverse reactions and healthcare admissions are likely to be prevented when healthcare providers limit and carefully monitor BZD prescribing, especially for those who are on other medications, including prescription opioids and antidepressants.

1. Introduction

After proton pump inhibitors, benzodiazepines (BZDs) are the second most commonly dispensed inappropriate medications for U.S. older adults [1]. The American Geriatric Society’s Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommends BZDs and non-BZD hypnotics (z-drugs) be avoided in all older adults [2]; however, BZD prescription rates for older adults have steadily increased over the past two decades [3,4]. Studies have also shown increased BZD and opioid co-prescribing rates, with female sex, a visit for chronic care, receipt of six or more concomitantly prescribed medications, clinical diagnoses of anxiety and pain, and opioid therapy ≥90 days as significant co-prescribing factors [5,6]. Co-prescribing of BZD and antidepressant medications for older adults is also common despite the fact that BZD use is not significantly associated with antidepressant adherence or any improvement in depressive symptoms but is associated with more medication-related adverse effects [7,8]. A study based on the National Health and Nutrition Examination Study found that the shares of older adults with central nervous system active polypharmacy (i.e., three or more medications) including BZDs (alprazolam in particular), opioids, selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors (SSRIs/SNRIs), anticholinergic, and antiepileptics (Gabapentin in particular) increased substantially between 2009 and 2020 [9].
The adverse effects of BZD use, as well as their co-use with opioids in older adults, have been extensively examined. For example, BZD use was associated with increased risk of aspiration and pneumonia [10,11], memory impairment and other cognitive defects [12,13,14], falls and fractures [15,16], impairment in driving skills [17], infections, pancreatitis, cancer [18,19], dependence [20], and all-cause mortality [21,22]. Co-use of BZD and opioids has also been found to increase frailty [23], risk of potentially lethal respiratory depression, falls, emergency department visits, and mortality [24,25]. An important predictor of opioid overdose is co-use of BZDs, and 14% of all overdose deaths involving prescription and/or illicitly manufactured opioids were found to also involve prescription and/or illicitly manufactured BZDs [26,27].
Concomitant use of BZDs and antidepressants has also been found to be associated with a significant increase in fracture risk [28]. Research has shown that co-use of BZDs, opioids, and tricyclic antidepressants increased falls, with significant effect sizes starting in late middle-age (e.g., 52 years) [29]. However, antidepressants have also been shown to lessen BZD withdrawal symptoms such as anxiety, sleep disturbances, and agitation when tapering dosage among long-term users, although the quality of evidence tends to be low [19,30].
A recent study of BZD cases age 50 and older reported to America’s poison centers showed that adverse drug reactions in cases involving BZDs comprise a small proportion of all BZD-involved cases, as more than three-quarters were intentional misuse or abuse cases, with 85% of these cases being suspected suicide attempts [31]. Probably because adverse reaction cases comprise a small proportion of all BZD cases reported to poison centers, little research has been carried out on them. Given the BZD-related risks for older adults, research on BZD adverse reaction cases reported to poison centers is needed to expand our understanding of the risk factors and effects of adverse reactions in older adults. In the present study, we examined two specific research questions: (1) what were the proportions and characteristics of the BZD adverse reaction cases age 50 and older that were admitted to a healthcare facility (HCF) and experienced major effects/death, and (2) was the co-use of opioids and/or antidepressants associated with greater odds of HCF admission and major effects/death?

2. Results

2.1. BZD Poisoning and Adverse Reaction Cases

The 2015–2022 NPDS included a total of 123,322 benzodiazepine-involved cases age 50 and older. The majority of these cases were suspected suicide attempts (65.1%), other intentional misuse or abuse cases (11.4%), and therapeutic errors or other unintentional misuse/abuse cases (21.1%). We identified a total of 2902 cases whose reason for exposure was coded as an adverse reaction; however, after excluding 4 confirmed nonexposed cases, 481 cases with effects unrelated to the exposure, 5 cases of unknown sex, and 1 indirectly reported death cases, we had 2411 cases. Of these 2411 cases, we focused on 1979 cases in which BZD was listed as the primary or secondary substance in the present study. Of the 1979 cases, 14.9% (n = 295) were admitted to an HCF. For the analysis of major effects/death, we focused only on 893 cases that were followed up. Of the 893 cases, 7.8% had major effects/death (n = 77; 71 major effect and 6 deaths). No significant difference was found in HCF admission rates (Pearson χ2 [df = 7] = 7.58, p = 0.371) and major effects/death rates (Pearson χ2 [df = 7] = 12.25, p = 0.093) by year for 2015–2020.

2.2. Comparison of Characteristics by HCF Admission Status

Table 1 shows that compared to those who were not admitted to an HCF, cases admitted to an HCF included a lower proportion of females and a higher proportion of those exposed at an HCF and the Northeastern region residents. Of all adverse reaction cases, 8.0% were exposed at an HCF; however, compared to 4.2% of those not admitted to an HCF, 29.2% of HCF-admitted patients were exposed to BZDs at an HCF. Compared to 22.4% of those not admitted to an HCF, 31.2% of HCF-admitted patients co-used opioids and/or antidepressants with BZDs. On average, HCF-admitted patients used significantly more substances concomitantly. Additional analysis showed no significant sex difference in the rates of co-use of opioids, antidepressants, and the number of all co-used substances. Compared to 1.3% of those not admitted to an HCF, 19.0% of HCF-admitted patients had major effects/death (Pearson χ2 [df = 1] = 211.16, p < 0.001).

2.3. Comparison of Characteristics by Major Effects/Death Status

Table 1 shows no age and sex differences between cases with and without major effects/death; however, compared to those without, those with major effects/death included a significantly higher proportion of cases that were exposed at a healthcare facility (12.6% vs. 45.5%). Compared to 25.4% of those without major effects/death, 37.8% of those with major effects/death co-used opioids and/or antidepressants. The rates of co-use of other substances did not significantly differ between those without and with major effects/death. Nearly three-quarters of those who had major effects/death were HCF-admitted patients.

2.4. HCF Admission and Major Effects/Death: Associations with Opioid/Antidepressant Co-Use

The second column of Table 2 shows that co-use of both opioids and antidepressants was associated with greater odds of HCF admission (aOR = 2.73 95% CI = 1.07–6.92), controlling for sex, exposure site, the number of co-used substances, and co-use of other substances. Of the covariates, female sex was associated with lower odds of HCF admission, while exposure at an HCF, higher numbers of co-used substances, and co-use of atypical antipsychotics, anticonvulsants, muscle relaxant, and Gabapentin were also associated with greater odds of HCF admission.
The third column of Table 2 shows that along with HCF admission, co-use of prescription opioids was associated with greater odds of major effects/death (aOR = 1.98, 95% CI = 1.06–3.70).

3. Discussion

We examined BZD adverse reaction cases age 50 and older that were reported to America’s Poison Centers in 2015 through 2022. These cases were a small proportion of all BZD-involved poisoning cases reported to poison control centers, as the majority were suspected suicide or other intentional misuse cases and therapeutic errors or other unintentional exposures. A notable finding is that 8% of the adverse reaction cases were exposed at an HCF, suggesting that BZDs for these cases were likely part of their medical care regimen. Nearly one out of six adverse reaction cases were admitted to a non-critical or critical care unit or a psychiatric facility for management, and more than one half of the HCF-admitted cases were admitted to a critical care unit. More than one half of BZD adverse reaction cases were not followed up, but of those who were followed up, 8.5% had major effects/death. As expected, those who were admitted to an HCF co-used significantly more other medications, especially prescription opioids and/or antidepressants.
Our findings related to HCF admission show that the concomitant use of BZDs with both opioids and antidepressants was associated with almost three times greater likelihood that adverse reaction cases would be HCF admitted; however, co-use of BZD with opioids alone or antidepressants alone was not significantly associated with HCF admission. Well-established research shows the risks of co-use of BZD and opioids [23,24,25,26,27] and antidepressants [28,29], and our findings provide further caution against co-prescribing all three medication classes. The finding that the number of substances co-used by those who were HCF-admitted was double the number co-used by those who were not HCF-admitted is also notable. The finding that more than one out of ten HCF-admitted cases co-used atypical antipsychotics is especially noteworthy. A study of a large cohort of Canadian older adults age 66 and older found that the risks of cardiovascular/cerebrovascular diseases was increased by 36% of atypical antipsychotic users for schizophrenia [32]. The significance of anticonvulsants, muscle relaxants, and Gabapentin as contributors to HCF admissions also suggests that those who were admitted to an HCF had poor physical and mental health. More research is needed to examine the physical and mental health effects of co-use of BZDs and atypical antipsychotics and these other medications.
Our findings related to medical outcomes show that the concomitant use of BZDs and opioids was associated with almost twice greater likelihood that the cases would have major effects/death. Previous poison center data-based studies showed an increased risk of death when prescription opioids and BZDs were used concomitantly [33,34]. In the present study, co-use of BZDs and antidepressants (without opioids) was not significantly associated with major effects/death (or HCF admission, as discussed earlier) among adverse reaction cases. As reviewed earlier [19,30], antidepressants may be helpful in lessening BZD withdrawal symptoms when tapering its use among long-term users. However, our findings are quite different from the findings related to BZD-involved suicide attempts or other intentional misuses, as co-use of antidepressants in these latter cases were found to be associated with greater odds of major effects/death [31]. These findings underscore differences between BZD adverse reaction cases and intentional misuse cases with respect to the effects of co-used antidepressants and other co-used medications. The discrepancy in the effects of these medications between the two groups is likely because intentional misuse cases, especially suicide attempt cases, often involve deliberate overdosing or self-poisoning of multiple substances, which also tend to result in significantly more serious medical outcomes in older than younger adults [35,36,37].
Interestingly, our findings show that the likelihood of HCF admission and major effects/death was not associated with age. We anticipated that, other things being equal, older age groups (e.g., those age 70 and older) would have worse medical outcomes. The lack of age group differences may be due to the under-reporting of death to poison centers and to the more than one-half of adverse reaction cases that were not followed up. The lack of age group difference may also be due to the fact that compared to intentional abuse/misuse cases, fewer adverse reaction cases have resulted in major effects/death [31]. Another reason may be because of historical BZD prescribing trends that uniquely affected older adults in their 70s and 80s. Individuals in these age groups are more likely to have been prescribed benzodiazepines earlier in life and experienced long-term use and resultant drug tolerance. BZDs have been used in mainstream medical care since 1960 and were initially greeted with enthusiasm by medical professionals, due to their substantially lower risk of causing respiratory depression compared to barbiturates and their proven effectiveness at managing anxiety and related disorders [38]. Initially, BZDs appeared to cause less dependence and have fewer side effects than other sedatives in common use; by the mid-1970s, they dominated lists of “most frequently prescribed” drugs [39]. Only in the 1980s did attitudes and prescription practices began to change, in light of growing evidence associating BZDs with misuse and long-term physiologic dependence even at normal prescribed doses [40].
HCF admission was lower among females, but the likelihood of major effects/death did not differ by sex. The reasons for sex differences in HCF admissions are not clear and call for more research on potential biological, medical, and other risk factors for HCF admissions. The lack of sex differences in medical outcomes is also a bit surprising. Pharmacokinetic and pharmacodynamic studies indicated substantially elevated incidence of adverse drug reactions in females due to higher blood drug concentrations and longer drug elimination times for BZDs, opioids, and many other pharmaceuticals compared to those observed for men [41,42]. More research with complete dose data is needed, as the findings may have been affected by dose reductions among females. Again, these findings may also be due to the under-reporting of deaths to poison centers and the low rate of follow-up.
Overall, this study confirms that BZD use, especially among older adults who take multiple other medications, can increase healthcare service use and result in negative medical outcomes. Consensus opinion remains strong that BZDs are overused, associated with dependence and other forms of harm, and that co-use with many other substances substantially increases the risk of harm. The regulatory environment has also shifted to discourage prescription of BZDs and encourage providers to decrease existing patient use [43]. At the same time, BZDs are still widely prescribed, and disproportionately so, to older adults [44]. Primary care providers drive some of these prescriptions due to operating under the burdens of seemingly insurmountable psychosocial problems faced by their patients, as well as a perceived lack of alternative treatments (i.e., SSRIs) with acceptably rapid onset and relative lack of side effects [45]. Further examination of BZDs’ negative health effects and more effective strategies to cut down BZD prescriptions are needed.
There are some limitations related to NPDS. First, the exposures that were reported to poison centers were not likely to be representative of all BZD poisoning cases, limiting the generalizability of the study findings. Second, as mentioned, deaths among cases are likely underestimates, as more cases were not followed up than were followed up. It is also not clear if all reported deaths were related to substance use or if other causes were involved. Third, data that are telephone-reported to poison centers without medical record validation and toxicological confirmation may compromise validity. Fourth, the lack of data on specific types of adverse reactions (e.g., delirium, respiratory depression, diarrhea, falls) and characteristics such as pre-existing health conditions, substance use history, and race/ethnicity precluded more detailed analyses. Fifth, a large proportion of cases had missing data on drug quantity and exposure chronicity, preventing analysis of these variables.

4. Materials and Methods

4.1. Data Source

The authors of this study obtained access to BZD-involved cases age 50 and older from America’s Poison Centers, which manages the National Poison Data System (NPDS). The NPDS contains data from 55 Poison Centers located in all 50 states, the District of Columbia, Puerto Rico, and US territories (see the NPDS website [https://poisoncenters.org/national-poison-data-system] (accessed on 6 August 2024) or the annual report by Gummin et al. [46] for detailed descriptions). The BZD cases that we examined in this study were from January, 2015 through December, 2022 and included only cases for which a BZD was listed as the primary or secondary (mostly after opioids) substance involved and the reason for exposure was an adverse reaction (i.e., not unintentional or intentional misuse or other/unknown reasons). The NPDS data list all co-used substances in each case, but the primary and secondary substances in the sequence of all involved substance tend to reflect the primary and secondary culprits. We focused on these two categories of BZD exposure cases to ensure that BZD was the primary or secondary reason for contacting poison centers. Although NPDS lists cases, not individuals, the extent to which these cases include duplicate individuals is minimal, as poison center specialists are trained to detect duplication and correct it as soon as it is discovered. Although not all cases of BZD intentional and unintentional misuse/abuse and adverse reaction are reported to poison centers, as reports to poison centers are voluntary, the NPDS is deemed the most comprehensive database for our research questions, as it includes human (and animal) exposures to all viral and bacterial agents and commercial chemical and drug products [46]. In accordance with the authors’ institutional review board (IRB) guidelines, analysis of these de-identified data was exempt from IRB review. Informed consent procedures did not apply for the secondary data analysis.

4.2. Measures

Adverse reaction as the exposure reason: The NPDS defines adverse drug reactions as “[having] occurred with normal, prescribed, labeled or recommended use of the product, as opposed to situations involving overdose, misuse, or abuse of the product”. The coding instructions for adverse reactions also specify that “the patient had an unwanted effect due to an allergic, hypersensitive, or idiosyncratic response to the active ingredient(s), inactive ingredient(s) or excipient of a drug, chemical, cosmetic, food or other substance”. It further specifies not to use this category for an interaction resulting from concomitant use of a contraindicated medication or food, as such interactions should be coded as therapeutic errors. Other NPDS exposure reason coding categories are intentional (suspected suicide attempt, misuse, abuse, and other intentional but unknown reasons), unintentional (therapeutic errors or other inadvertent/unintentional misuse), unknown/undetermined, and other.
Healthcare facility admission: The NPDS lists the following management/care sites of human exposure cases: managed on site (i.e., initial call or exposure site) but not at a healthcare facility (HCF); treated/evaluated and released from an HCF; admitted to a psychiatric facility; admitted to a noncritical care unit; admitted to critical care; and refused poison center’s referral to an HCF, no-show, or left the HCF against medical advice (AMA). In this study, we grouped these into two categories: admission to noncritical and critical care unit or to a psychiatric facility (=1; referred to as HCF admission hereafter) versus all others (=0; on-site management, treatment/evaluation/release, HCF referral refusal, no-show, and discharge AMA).
Medical outcomes: NPDSs’ medical outcome categories for human exposure include no effect; minor effect; moderate effect; major effect; and death. While the moderate effect category comprises “signs or symptoms that were not life-threatening or had no residual disability or disfigurement”, major effects include “signs or symptoms that were life-threatening or resulted in significant residual disability or disfigurement” [46]. We excluded indirectly reported deaths (in which poison centers acquired information from medical examiners or media or states’ vital statistics but did not manage the case themselves [46]) in this study. Then, we combined these outcomes into two categories: major effects or death (=1) versus no major effects/death (=0). Although NPDS also assigns expected outcomes (judged to be nontoxic, minimal/no more than minor clinical effects possible, or potentially toxic) for the cases that were not followed, we excluded the non-followed cases from our multivariable analysis of major effects/death.
Co-used prescription opioids and antidepressants: The NPDS sections on prescription opioids contain 23 codes and prescription antidepressants contain 31 codes. We created a four-category variable to denote co-use of opioids and/or antidepressants with BZD: (1) no co-use of opioids or antidepressants; (2) co-use of opioids but not antidepressants; (3) co-use of antidepressants but not opioids; and (4) co-use of both opioids and antidepressants. Other co-used medications included atypical antipsychotics; drugs for cardiovascular diseases (33 codes); antihistamines (12 codes); anticonvulsants (16 codes); muscle relaxants (8 codes), Gabapentin; anxiolytics other than BZDs; and other analgesics. We chose to include these other medications as they were co-used by some (>2.5%) BZD cases and may also have contributed to HCF admission and medical outcomes.
Other covariates in multivariable models included the following: gender, exposure site, and the NPDS-provided number of all substances involved in each case. We reported age, call sites, and the census region for descriptive purposes only.

4.3. Analysis

All analyses were conducted with Stata 18/MP (Stata Corp, College Station, TX, USA). First, based on 8 years of pooled data, we examined changes over these years in the numbers of adverse reaction cases and percentages of HCF admission and major effects/death among those who were followed up. Second, we used descriptive statistics (Pearson’s χ2 or independent-sample t tests) to compare cases by HCF admission and major effects/death with respect to demographics, exposure-related characteristics, and co-used substances. Third, we fitted two multivariable logistic regression models to examine demographics and co-used opioids, antidepressant medications, and other drugs that may have been associated with HCF admission and major effects/death, respectively. Given the large number of co-used medications besides prescription opioids and antidepressants, we used backward elimination methods to remove those with p > 0.10. The final model for HCF admission included, along with prescription opioids and antidepressants, atypical antipsychotics, anticonvulsants, muscle relaxants, and Gabapentin as the covariates. The final model for major effects/death did not include any co-used medications besides prescription opioids and antidepressants. The logistic regression results are reported as adjusted odds ratios (aORs) with 95% CIs. Statistical significance was set at p < 0.05.

5. Conclusions

This study shows that the concomitant use of BZD, opioids, and antidepressants substantially increases the risk of HCF admissions among BZD adverse reaction cases age 50 and older that were reported to poison centers. Co-use of opioids and BZDs also contributed to greater likelihood of major effects/death. Despite the study’s limitations, our findings have the following implications. First, adverse reactions and the need for HCF admissions are likely to be prevented when healthcare providers limit and carefully monitor BZD prescribing, especially for those who are on prescription opioids, antidepressants, atypical antipsychotics, and other medications. Second, given that HCFs consisted of almost one-tenth of the exposure sites of the adverse reaction cases, more concerted efforts to better train healthcare providers and reduced BZD use at HCFs are warranted. Third, integrated physical and behavioral health services, as opposed to pharmacotherapy alone, may be better suited for older adults who suffer from depression, anxiety, pain, and other physical health problems. Fourth, more research on BZD-involved adverse reactions in older adults is needed, considering their physical health conditions, comorbidity, co-used substances, drug quantity, and exposure chronicity.

Author Contributions

Data acquisition and overall guidance: S.D.B.; study conceptualization: B.Y.C.; data management: N.G.C.; data analysis and interpretation: N.G.C. and C.N.M.; manuscript draft: B.Y.C. and N.G.C.; final editing: B.Y.C., N.G.C., S.D.B. and C.N.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by grant P30AG066614, which was awarded to the Center on Aging and Population Sciences at The University of Texas at Austin by the National Institute on Aging. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Institutional Review Board Statement

This study based on de-identified data was deemed to be exempt by the authors’ institutional review boards.

Informed Consent Statement

Not applicable.

Data Availability Statement

The America’s Poison Centers (APC) releases the National Poison Data System (NPDS) to investigators following a review of data request. The authors do not have permission to make the NPDS dataset used in this study available to other investigators.

Acknowledgments

The America’s Poison Centers (APC) made the National Poison Data System (NPDS) available to the authors for this study. This study’s findings and conclusions are those of the authors alone and do not necessarily represent the official position of the APC or participating poison control centers.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

References

  1. Fralick, M.; Bartsch, E.; Ritchie, C.S.; Sacks, C.A. Estimating the use of potentially inappropriate medications among older adults in the United States. J. Am. Geriatr. Soc. 2020, 68, 2927–2930. [Google Scholar] [CrossRef]
  2. American Geriatrics Society. American Geriatrics Society 2019 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J. Am. Geriatr. Soc. 2019, 67, 674–694. [Google Scholar] [CrossRef]
  3. Agarwal, S.D.; Landon, B.E. Patterns in outpatient benzodiazepine prescribing in the United States. JAMA Netw. Open 2019, 2, e187399, Erratum in JAMA Netw. Open 2019, 2, e191203. [Google Scholar] [CrossRef] [PubMed]
  4. Hwang, C.S.; Kang, E.M.; Kornegay, C.J.; Staffa, J.A.; Jones, C.M.; McAninch, J.K. Trends in the concomitant prescribing of opioids and benzodiazepines, 2002–2014. Am. J. Prev. Med. 2016, 51, 151–160. [Google Scholar] [CrossRef]
  5. Rhee, T.G. Coprescribing of benzodiazepines and opioids in older adults: Rates, correlates, and national trends. J. Gerontol. A Biol. Sci. Med. Sci. 2019, 74, 1910–1915. [Google Scholar] [CrossRef] [PubMed]
  6. Gerlach, L.B.; Olfson, M.; Kales, H.C.; Maust, D.T. Opioids and other central nervous system-active polypharmacy in older adults in the United States. J. Am. Geriatr. Soc. 2017, 65, 2052–2056. [Google Scholar] [CrossRef]
  7. Altmann, H.; Stahl, S.T.; Gebara, M.A.; Lenze, E.J.; Mulsant, B.H.; Blumberger, D.M.; Reynolds, C.F., 3rd; Karp, J.F. Coprescribed benzodiazepines in older adults receiving antidepressants for anxiety and depressive disorders: Association with treatment outcomes. J. Clin. Psychiatry 2020, 81, 20m13283. [Google Scholar] [CrossRef]
  8. Leggett, A.; Kavanagh, J.; Zivin, K.; Chiang, C.; Kim, H.M.; Kales, H.C. The association between benzodiazepine use and depression outcomes in older veterans. J. Geriatr. Psychiatry Neurol. 2015, 28, 281–287. [Google Scholar] [CrossRef] [PubMed]
  9. Terman, S.W.; Niznik, J.D.; Growdon, M.E.; Gerlach, L.B.; Burke, J.F. Secular trends in central nervous system-active polypharmacy among serial cross-sections of US adults, 2009–2020. Drugs Aging 2023, 40, 941–951. [Google Scholar] [CrossRef]
  10. Pu, D.; Wong, M.C.H.; You, E.M.L.; Chan, K.M.K. Profiles of polypharmacy in older adults and medication associations with signs of aspiration. Expert Rev. Clin. Pharmacol. 2021, 14, 643–649. [Google Scholar] [CrossRef]
  11. Rajamaki, B.; Hartikainen, S.; Tolppanen, A.M. Psychotropic drug-associated pneumonia in older adults. Drugs Aging 2020, 37, 241–261. [Google Scholar] [CrossRef] [PubMed]
  12. Vgontzas, A.N.; Kales, A.; Bixler, E.O. Benzodiazepine side effects: Role of pharmacokinetics and pharmacodynamics. Pharmacology 1995, 51, 205–223. [Google Scholar] [CrossRef] [PubMed]
  13. Takada, M.; Fujimoto, M.; Hosomi, K. Association between benzodiazepine use and dementia: Data mining of different medical databases. Int. J. Med. Sci. 2016, 13, 825–834. [Google Scholar] [CrossRef] [PubMed]
  14. Liu, L.; Jia, L.; Jian, P.; Zhou, Y.; Zhou, J.; Wu, F.; Tang, Y. The effects of benzodiazepine use and abuse on cognition in the elders: A systematic review and meta-analysis of comparative studies. Front. Psychiatry 2020, 11, 00755. [Google Scholar] [CrossRef]
  15. McDonald, E.M.; Caslangen, J. Benzodiazepine use and falls in older adults: Is it worth the risk? Res. Gerontol. Nurs. 2019, 12, 214–216. [Google Scholar] [CrossRef]
  16. Finkle, W.D.; Der, J.S.; Greenland, S.; Adams, J.L.; Ridgeway, G.; Blaschke, T.; Wang, Z.; Dell, R.M.; VanRiper, K.B. Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults. J. Am. Geriatr. Soc. 2011, 59, 1883–1890. [Google Scholar] [CrossRef]
  17. van der Sluiszen, N.N.J.J.M.; Vermeeren, A.; Verster, J.C.; van de Loo, A.J.A.E.; van Dijken, J.H.; Veldstra, J.L.; Brookhuis, K.A.; de Waard, D.; Ramaekers, J.G. Driving performance and neurocognitive skills of long-term users of benzodiazepine anxiolytics and hypnotics. Hum. Psychopharmacol. 2019, 34, e2715. [Google Scholar] [CrossRef]
  18. Brandt, J.; Leong, C. Benzodiazepines and Z-Drugs: An updated review of major adverse outcomes reported on in epidemiologic research. Drugs R D 2017, 17, 493–507. [Google Scholar] [CrossRef]
  19. Peng, T.R.; Yang, L.J.; Wu, T.W.; Chao, Y.C. Hypnotics and risk of cancer: A meta-analysis of observational studies. Medicina 2020, 56, 513. [Google Scholar] [CrossRef]
  20. Robertson, S.; Peacock, E.E.; Scott, R. Benzodiazepine use disorder: Common questions and answers. Am. Fam. Physician 2023, 108, 260–266. [Google Scholar]
  21. Palmaro, A.; Dupouy, J.; Lapeyre-Mestre, M. Benzodiazepines and risk of death: Results from two large cohort studies in France and UK. Eur. Neuropsychopharmacol. 2015, 25, 1566–1577. [Google Scholar] [CrossRef]
  22. Parsaik, A.K.; Mascarenhas, S.S.; Khosh-Chashm, D.; Hashmi, A.; John, V.; Okusaga, O.; Singh, B. Mortality associated with anxiolytic and hypnotic drugs-A systematic review and meta-analysis. Aust. N. Z. J. Psychiatry 2016, 50, 520–533. [Google Scholar] [CrossRef]
  23. Bergen, A.W.; Cil, G.; Sargent, L.J.; Dave, C.V. Frailty risks of prescription analgesics and sedatives across frailty models: The Health and Retirement Study. Drugs Aging 2022, 39, 377–387. [Google Scholar] [CrossRef] [PubMed]
  24. Boon, M.; van Dorp, E.; Broens, S.; Overdyk, F. Combining opioids and benzodiazepines: Effects on mortality and severe adverse respiratory events. Ann. Palliat. Med. 2020, 9, 542–557. [Google Scholar] [CrossRef]
  25. Yarborough, B.J.H.; Stumbo, S.P.; Stoneburner, A.; Smith, N.; Dobscha, S.K.; Deyo, R.A.; Morasco, B.J. Correlates of benzodiazepine use and adverse outcomes among patients with chronic pain prescribed long-term opioid therapy. Pain Med. 2019, 20, 1148–1155. [Google Scholar] [CrossRef] [PubMed]
  26. Blanco, C.; Han, B.; Jones, C.M.; Johnson, K.; Compton, W.M. Prevalence and correlates of benzodiazepine use, misuse, and use disorders among adults in the United States. J. Clin. Psychiatry 2018, 79, 18m12174. [Google Scholar] [CrossRef]
  27. Pierce, J.; Moser, S.; Hassett, A.L.; Brummett, C.M.; Christianson, J.A.; Goesling, J. Influence of abuse history on concurrent benzodiazepine and opioid use in chronic pain patients. J. Pain 2019, 20, 473–480. [Google Scholar] [CrossRef]
  28. Yang, B.R.; Lee, E.; Hwang, B.S.; Lee, S.H.; Kang, Y.J.; Jung, S.Y. Risk of fracture in antidepressant users with concurrent use of benzodiazepines: A self-controlled case-series analysis. Bone 2021, 153, 116109. [Google Scholar] [CrossRef] [PubMed]
  29. Cordovilla-Guardia, S.; Molina, T.B.; Franco-Antonio, C.; Santano-Mogena, E.; Vilar-López, R. Association of benzodiazepines, opioids and tricyclic antidepressants use and falls in trauma patients: Conditional effect of age. PLoS ONE 2020, 15, e0227696. [Google Scholar] [CrossRef]
  30. Baandrup, L.; Ebdrup, B.H.; Rasmussen, J.Ø.; Lindschou, J.; Gluud, C.; Glenthøj, B.Y. Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users. Cochrane Database Syst. Rev. 2018, CD011481. [Google Scholar] [CrossRef]
  31. Choi, N.G.; Choi, B.Y.; Marti, C.N.; Baker, S.D. Intentional benzodiazepine poisoning in older adults reported to United States poison centers. Clin. Toxicol. 2024, 62, 174–182. [Google Scholar] [CrossRef] [PubMed]
  32. Gummin, D.D.; Mowry, J.B.; Beuhler, M.C.; Spyker, D.A.; Rivers, L.J.; Feldman, R.; Brown, K.; Nathaniel, P.T.P.; Bronstein, A.C.; Weber, J.A. 2021 Annual report of the National Poison Data System© (NPDS) from America’s poison centers: 39th annual report. Clin. Toxicol. 2022, 60, 1381–1643. [Google Scholar] [CrossRef]
  33. Perreault, S.; Boivin Proulx, L.A.; Brouillette, J.; Jarry, S.; Dorais, M. Antipsychotics and risks of cardiovascular and cerebrovascular diseases and mortality in community-dwelling older adults. Pharmaceuticals 2024, 17, 178. [Google Scholar] [CrossRef] [PubMed]
  34. Calcaterra, S.L.; Severtson, S.G.; Bau, G.E.; Margolin, Z.R.; Bucher-Bartelson, B.; Green, J.L.; Dart, R.C. Trends in intentional abuse or misuse of benzodiazepines and opioid analgesics and the associated mortality reported to poison centers across the United States from 2000 to 2014. Clin. Toxicol. 2018, 56, 1107–1114. [Google Scholar] [CrossRef]
  35. Choi, N.G.; Choi, B.Y.; DiNitto, D.M.; Marti, C.N.; Baker, S.D. Exposure reasons, other substance use, and medical outcomes of poison control center cases aged 50+ involving opioids, 2015–2020. Clin. Toxicol. 2022, 60, 362–370. [Google Scholar] [CrossRef]
  36. Fusaroli, M.; Pelletti, G.; Giunchi, V.; Pugliese, C.; Bartolucci, M.; Necibi, E.N.; Raschi, E.; De Ponti, F.; Pelotti, S.; Poluzzi, E. Deliberate self-poisoning: Real-time characterization of suicidal habits and toxidromes in the Food and Drug Administration Adverse Event Reporting System. Drug Saf. 2023, 46, 283–295. [Google Scholar] [CrossRef] [PubMed]
  37. Francis, M.; Spiller, H.A.; Badeti, J.; Funk, A.R.; Casavant, M.J.; Michaels, N.L.; Zhu, M.; Smith, G.A. Suspected suicides and nonfatal suicide attempts involving antidepressants reported to United States poison control centers, 2000–2020. Clin. Toxicol. 2022, 60, 818–826. [Google Scholar] [CrossRef]
  38. Ybanez, L.; Spiller, H.A.; Badeti, J.; Casavant, M.J.; Rine, N.; Michaels, N.L.; Zhu, M.; Smith, G.A. Suspected suicides and suicide attempts involving antipsychotic or sedative-hypnotic medications reported to America’s Poison Centers, 2000–2021. Clin. Toxicol. 2023, 61, 294–304. [Google Scholar] [CrossRef]
  39. Rosenbaum, J.F. Attitudes toward benzodiazepines over the years. J. Clin. Psychiatry 2005, 66 (Suppl. S2), 4–8. [Google Scholar]
  40. Wick, J.Y. The history of benzodiazepines. Consult. Pharm. 2013, 28, 538–548. [Google Scholar] [CrossRef]
  41. Lader, M. History of benzodiazepine dependence. J. Subst. Abuse Treat. 1991, 8, 53–59. [Google Scholar] [CrossRef]
  42. Farkouh, A.; Riedl, T.; Gottardi, R.; Czejka, M.; Kautzky-Willer, A. Sex-related differences in pharmacokinetics and pharmacodynamics of frequently prescribed drugs: A review of the literature. Adv. Ther. 2020, 37, 644–655. [Google Scholar] [CrossRef]
  43. Zucker, I.; Prendergast, B.J. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol. Sex Differ. 2020, 11, 32. [Google Scholar] [CrossRef]
  44. Kroenke, K.; Hirschtritt, M.E. Walking the benzodiazepine high wire. Psychiatr. Serv. 2023, 74, 73–75. [Google Scholar] [CrossRef] [PubMed]
  45. Llorente, M.D.; David, D.; Golden, A.G.; Silverman, M.A. Defining patterns of benzodiazepine use in older adults. J. Geriatr. Psychiatry Neurol. 2000, 13, 150–160. [Google Scholar] [CrossRef] [PubMed]
  46. Anthierens, S.; Habraken, H.; Petrovic, M.; Christiaens, T. The lesser evil? Initiating a benzodiazepine prescription in general practice: A qualitative study on GPs’ perspectives. Scand. J. Prim. Health Care 2007, 25, 214–219. [Google Scholar] [CrossRef] [PubMed]
Table 1. Characteristics of benzodiazepine adverse reaction cases age 50+ admitted to a healthcare facility (HCF) and with major effects/death.
Table 1. Characteristics of benzodiazepine adverse reaction cases age 50+ admitted to a healthcare facility (HCF) and with major effects/death.
All BZD Adverse Reaction Cases
(1979, 100%)		HCF AdmissionMedical Outcome
among Those Who Were Followed Up
No Admission
1684 (85.1%)		Admission
295 (14.9%)		pNo Major Effect
816 (91.4%)		Major Effect/
Death
77 (8.5%)		p
Age group (years, %) 0.441 0.401
 50–5932.632.035.9 34.232.5
 60–6930.029.930.2 28.837.7
 70–7922.422.919.3 20.216.9
 80+ 15.115.114.6 16.813.0
Female (%) 66.567.859.00.00465.454.50.062
Exposure site <0.001 <0.001
 Own residence90.594.468.5 85.753.2
 Healthcare facility7.94.229.2 12.645.5
 Other1.61.42.4 1.71.3
Call site (%) <0.001 <0.001
 Own residence71.083.00.8 52.73.9
 Healthcare facility23.210.897.0 42.489.6
 Other5.86.22.2 4.96.5
Region (%) <0.001 <0.001
 Northeast14.913.525.9 13.129.9
 Midwest17.216.620.7 21.416.9
 South33.933.834.9 29.833.8
 West33.735.818.5 34.918.2
 Puerto Rico0.40.20
No. of all substances co-used, M (SE) 1.85 (1.26)1.75 (1.06)3.78 (2.81)<0.0011.93 (1.43)2.39 (1.67)0.005
Co-used substances (%)
Opioid and antidepressant <0.001 0.010
 Neither76.377.668.8 74.662.3
 Prescription opioid alone13.012.516.3 13.424.7
 Antidepressant alone9.29.010.5 10.07.8
 Both opioid and antidepressant1.51.04.4 2.05.2
Atypical antipsychotics6.25.012.5<0.0017.07.80.815
Cardiovascular drugs4.24.05.40.2694.22.60.762
Antihistamine4.44.54.41.0004.42.60.785
Anticonvulsant3.12.38.1<0.0015.05.21.000
Muscle relaxant2.92.45.80.0043.32.61.000
Gabapentin2.72.07.1<0.0013.43.90.744
Anxiolytics3.13.03.40.7153.25.20.319
Healthcare facility (HCF) service use (%) <0.001 <0.001
 No HCF use (managed on site)61.972.80 43.82.5
 Treated/evaluated/released10.712.50 21.023.4
 Admitted to psychiatric facility0.503.1 0.72.6
 Admitted to noncritical care7.8052.2 15.820.8
 Admitted to critical care6.7044.7 10.749.4
 Refused referral/AMA12.514.70 8.11.3
Medical outcomes (%) <0.001
 No/minor effect23.524.417.9
 Moderate effect17.810.957.3
 Major effect3.61.216.9
 Death0.302.0
 Unable to follow54.963.55.8
p-values were calculated based on Pearson’s χ2 tests for categorical variables and independent sample t test for the number of co-used substances.
Table 2. Associations of healthcare admission and major effects/death with concomitant use of opioids and/or antidepressants: Results from logistic regression models.
Table 2. Associations of healthcare admission and major effects/death with concomitant use of opioids and/or antidepressants: Results from logistic regression models.
Healthcare Admission vs.
No Admission
aOR (95% CI)		Major Effects/Death vs.
No Major Effect
aOR (95% CI)
Female vs. Male0.70 (0.53–0.93) *0.67 (0.41–1.10)
Exposed at a healthcare facility or other places vs. at home9.37 (6.67–13.16) ***
Admitted to healthcare facility 6.66 (3.90–11.37) ***
No. of all substances co-used1.19 (1.04–1.35) **1.04 (0.90–1.22)
Opioid and antidepressant use vs. neither use
 Prescription opioid only1.03 (0.69–1.56)1.98 (1.06-3.70) *
 Antidepressant only1.09 (0.67–1.78)0.79 (0.29-2.13)
 Both opioid and antidepressant2.73 (1.07–6.92) *1.69 (0.47-6.14)
Atypical antipsychotics2.09 (1.28–3.41) **
Anticonvulsant3.01 (1.63–5.56) ***
Muscle relaxant2.37 (1.22–4.59) *
Gabapentin2.93 (1.53–5.61) **
Model statisticsN = 1979; LR χ2 = 247.73; p < 0.001; pseudo R2 = 0.15N = 893; LR χ2 = 70.93; p < 0.001; pseudo R2 = 0.14
* p < 0.05; ** p < 0.01; *** p < 0.001.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Choi, B.Y.; Choi, N.G.; Marti, C.N.; Baker, S.D. Benzodiazepine Adverse Reaction Cases Age 50 and Older Reported to the U.S. Poison Centers: Healthcare Use and Major Medical Effects. Pharmacoepidemiology 2024, 3, 285-296. https://doi.org/10.3390/pharma3030019

AMA Style

Choi BY, Choi NG, Marti CN, Baker SD. Benzodiazepine Adverse Reaction Cases Age 50 and Older Reported to the U.S. Poison Centers: Healthcare Use and Major Medical Effects. Pharmacoepidemiology. 2024; 3(3):285-296. https://doi.org/10.3390/pharma3030019

Chicago/Turabian Style

Choi, Bryan Y., Namkee G. Choi, C. Nathan Marti, and S. David Baker. 2024. "Benzodiazepine Adverse Reaction Cases Age 50 and Older Reported to the U.S. Poison Centers: Healthcare Use and Major Medical Effects" Pharmacoepidemiology 3, no. 3: 285-296. https://doi.org/10.3390/pharma3030019

APA Style

Choi, B. Y., Choi, N. G., Marti, C. N., & Baker, S. D. (2024). Benzodiazepine Adverse Reaction Cases Age 50 and Older Reported to the U.S. Poison Centers: Healthcare Use and Major Medical Effects. Pharmacoepidemiology, 3(3), 285-296. https://doi.org/10.3390/pharma3030019

Article Metrics

Back to TopTop