Use Of Central Nervous System Depressants Research Articles

Would CNS depressants cause paradoxical aggressive driving behaviors?

Aggressive driving consists of risky driving behaviors and traffic infractions performed with ill intent or disregard for other road users’ safety and associated with negative emotions like anger and frustration. Such behaviors may include tailgating, speeding, weaving through traffic, running red lights, and others. While evaluating the risk of drugs that decrease inhibitions or have central nervous system (CNS) stimulant effects like alcohol and cocaine for aggressive driving behaviors makes sense, doing the same with benzodiazepines and other CNS depressants may appear illogical since the drugs would have anti-aggressive effects, inducing sedation and stabilizing mood. However, unexpected aggressive/agitated episodes, albeit rarely, have been reported after the use of certain CNS depressants. The purpose of this study is to evaluate whether CNS depressants may lead to paradoxical aggressive driving behaviors by reviewing case reports of suspected impaired drivers tested positive for CNS depressants other than ethanol. This research examined driving while intoxicated (DWI) or under the influence of drugs (DUID) cases submitted in 2019 and tested positive in blood for CNS depressants other than ethanol only (i.e., benzodiazepines, barbiturates, muscle relaxants, antipsychotics, and anticonvulsants). The blood samples were submitted by the Houston Police Department and were subsequently analyzed for alcohol and drugs by Houston Forensic Science Center and a reference laboratory. Toxicological findings, demographic information as well as driving behaviors and the standardized field sobriety test (SFST) observations of impairment described in the police reports were evaluated. Among 1214 DWI/DUID cases in which offense occurred in 2019 and blood samples were tested positive for one or more drugs, just 50 drivers were tested positive for CNS depressants only. Twenty-five drugs/metabolites were identified with benzodiazepines/metabolites being the most prevalent, in 72% of the 50 cases. The majority exhibited typical behaviors expected from CNS depressant use: 86% of the drivers had non-violent attitudes and 91% (39/43) showed horizontal gaze nystagmus (HGN). All ( n = 35) showed one or more clues in Walk and Turn (WAT) and except 2, in One-leg Stand (OLS). Traffic incidents included weaving (22%), hitting an object or another vehicle (38%), stopping in a moving lane (18%). However, a few drivers exhibited agitation. Below are two case examples: – case 1: 58-year-old female driver failed to signal a lane change, accelerating away from the patrol car and yelling. When officers encountered the driver, she exhibited uncooperative and erratic behaviors. Officer could only administer HGN, and she showed 2/6 clues. Blood sample was positive for alprazolam at 13 ng/mL and meprobamate at 2.5 μg/mL; – case 2: 24-year-old female driver stopped in a moving lane of traffic. Upon officers approaching the vehicle, she began to speak to officers in an agitated voice. Officers observed the driver could not keep balance. SFST results included 4/6 HGN, 3/4 OLS, and 6/8 WAT clues. Blood sample was positive for alprazolam at 120 ng/mL and for zolpidem at 100 ng/mL; Considering a multitude of social, environmental, and biological factors that can influence one's driving performance, the findings should be taken with caution and alternative interpretations other than drug effects should be considered. The research confirmed that aggressive behaviors among CNS depressant positive drivers are rare and idiosyncratic. These case examples nonetheless demonstrated how different drugged driving behaviors can be and more research is needed to further clarify the association.

The effect of cognitive function and central nervous system depressant use on mortality-A prospective observational study of previously hospitalised older patients.

Older patients are often users of prolonged Central Nervous System Depressants (CNSD) (Z-hypnotics, benzodiazepines and opioids), which may be associated with reduced cognition. The long-term effects of CNSD use and reduced cognitive function in older patients are unclear. The aim of this study was to examine whether cognitive function and CNSD use at baseline hospitalisation were associated with all-cause mortality two years after discharge. We conducted a prospective observational study, including baseline data (2017-2018) from previously hospitalised older patients (65-90 years), assessing all-cause mortality two years after discharge. We used logistic regression to assess the primary outcome, all-cause mortality two years after baseline hospitalisation. The primary predictors were cognitive function measured by The Mini Mental State Examination (MMSE) and prolonged CNSD use (continuous use ≥ 4 weeks). Adjustment variables: age, gender, education, the Hospital Anxiety and Depression Scale (HADS) and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G), using receiver operating characteristics (ROC) to compare the predictive power of the models. In a sub-analysis we used, the Neurobehavioural Cognitive State Examination (Cognistat) and the Clock Drawing Test. Two years after discharge, out of 246 baseline patients, 43 were deceased at follow-up, among these 27 (63%) were CNSD users, and 16 (36%) were non-users at baseline, (p = 0.002). In the multivariable models cognitive function (MMSE score) was a predictor of mortality (OR 0.81 (95% CI 0.69; 0.96), p = 0.014). CNSD use was associated with mortality (OR 2.71 (95% CI 1.06; 6.95), p = 0.038), with ROC AUC: 0.74-0.77 for these models. Results using Cognistat supported the findings. The Clock Drawing Test was not significant predictor of mortality. Two years after discharge from the hospital, older patients with reduced cognitive function and CNSD use during hospital stay had higher mortality. This underlines that inappropriate (prolonged and concurrent) use of CNSDs should be avoided by older patients, particularly in patients with reduced cognitive function. NCT03162081, 22 May 2017.

Central Nervous System Depressants and Risk of Hospitalization due to Community-Acquired Pneumonia in very Old Patients.

Central Nervous System (CNS) depressants like antipsychotics, opioids, benzodiazepines and zolpidem are frequently used by patients of a wide range of ages. Uncertainty remains about their effect in very old adults (>80 years old) and their potential for pharmacodynamic and pharmacokinetic drug-drug interactions in this population. To assess if the use of CNS depressants is associated with a higher risk of hospitalization due to community-acquired pneumonia (CAP) in very old patients. In this prospective study, 362 patients over 80 years of age who had been consequently admitted to the general ward of a teaching hospital were examined. Each patient was assessed, by our pharmacovigilance team within 24 hours of admission, to identify outpatient medication use and potential drug-drug interactions. The overall use of CNS depressants as a group was not associated with a higher risk of admission due to CAP in very old patients (55% vs. 49%; OR=1.28 [0.76-2.16], p=0.34). However, the use of antipsychotics was associated with a higher rate of admissions due to CAP in this population (OR=1.98 [1.10-3.57], p=0.02). No association was seen between opioids (p=0.27), zolpidem (p=0.83), or benzodiazepines (p=0.15) and the rate of admissions due to CAP in these patients. Moreover, pharmacodynamic or pharmacokinetic interactions leading to CNS depression were equally found in patients admitted for CAP and those admitted for other reasons. The use of antipsychotics in very old adults was associated with an increased risk of hospital admission due to CAP. This suggests that the use of these medications in this population should be done with caution. No association was observed with opioids, benzodiazepines and zolpidem with the latter outcome.

Association between Use of Methadone, Other Central Nervous System Depressants, and QTc Interval-Prolonging Medications and Risk of Mortality in a Large Cohort of Women Living with or at Risk for Human Immunodeficiency Virus Infection.

To evaluate the association between use of methadone, other central nervous system (CNS) depressants, and QTc interval-prolonging medications and risk of mortality among human immunodeficiency virus (HIV)-infected and at-risk HIV-uninfected women. Multicenter, prospective, observational cohort study (Women's Interagency HIV Study [WIHS]). A total of 4150 women enrolled in the WIHS study between 1994 and 2014 who were infected (3119 women) or not infected (1031 women) with HIV. Data on medication utilization were collected from all study participants via interviewer-administered surveys at 6-month intervals (1994-2014). Mortality was confirmed by National Death Index data. With age defining the time scale for the analysis, Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause mortality in HIV-infected and -uninfected women and non-acquired immunodeficiency syndrome (AIDS) deaths in HIV-infected women. A total of 1046 deaths were identified, of which 429 were considered non-AIDS deaths. Use of benzodiazepines, CNS depressants (excluding methadone), and number of medications with conditional QTc interval-prolonging effects were each associated with all-cause mortality in multivariate models of HIV-infected women: hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01-1.60, p=0.037; HR 1.61, 95% CI 1.35-1.92, p<0.0001; and HR 1.15 per drug, 95% CI 1.00-1.33, p=0.047, respectively. Other explanatory variables for all-cause mortality in this model included HIV viral load, CD4+ cell count, renal function, hemoglobin and albumin levels, HIV treatment era, employment status, existence of depressive symptoms, ever use of injection drugs, and tobacco smoking. Of interest, use of CNS depressants (excluding methadone) was also associated with non-AIDS deaths (HR 1.49, 95% CI 1.49-2.2, p<0.0001). Although use of benzodiazepines and conditional QT interval-prolonging medications were associated with increased risk of non-AIDS mortality (HR 1.32 and 1.25, respectively), the effect was not statistically significant (p>0.05). In this cohort of HIV-infected and at-risk HIV-uninfected women, use of benzodiazepines, CNS depressants, and conditional QTc interval-prolonging medications were associated with a higher risk of mortality independent of methadone and other well-recognized mortality risk factors. Care must be taken to assess risk when prescribing these medications in this underserved and at-risk patient population.

Acute Substance Use as a Warning Sign for Suicide Attempts: A Case-Crossover Examination of the 48 Hours Prior to a Recent Suicide Attempt.

The extent to which specific categories of acute substance use are short-term risk factors, or warning signs, for suicide attempts is unknown. The aim of the current study was to quantify the near-term effects of sole use and co-use of substances on medically attended suicide attempts. The current study used a case-crossover design, comparing substance use within the 24 hours prior to a suicide attempt (case day) to the control day, the matched 24 hours the day prior to the case day. Participants were 363 recent suicide attempters presenting to a Level 1 trauma hospital between October 2008 and April 2014. A timeline follow-back methodology was used to assess acute exposures within the 48 hours before the suicide attempt. Conditional logistic regression was used to report odds ratios (ORs) and 95% confidence intervals (CIs). Results indicated that patients were at increased odds of attempting suicide after drinking alcohol within a 24-hour period (OR = 4.40; 95% CI, 2.31-8.40) and using a drug from another class of substances with central nervous system (CNS) depressant characteristics (sedatives/anxiolytics and opioids; OR = 2.82; 95% CI, 1.13-7.01), after adjustment for other acute substance use. The acute use of cannabis and CNS stimulants (stimulants/amphetamines and cocaine) was not uniquely associated with suicide attempt. Co-use of alcohol synergized effects of other CNS depressants (OR = 8.76; 95% CI, 1.02-75.44). Findings suggest the importance of considering acute alcohol use and use of CNS depressants, and the concurrent use of both substances, when evaluating short-term risk for suicide attempts in clinical settings.

A Longitudinal Study of Multiple Drug Use and Overdose Among Young People Who Inject Drugs.

To determine the association between multiple drug use and nonfatal overdose among young people (younger than 30 years) who inject drugs. We completed a longitudinal study of 173 injection drug users younger than 30 years living in San Francisco, California, between April 2012 and February 2014. The odds of nonfatal overdose increased significantly as heroin and benzodiazepine pill-taking days increased and when alcohol consumption exceeded 10 drinks per day compared with 0 drinks per day. Heroin, benzodiazepine, and alcohol use were independently associated with nonfatal overdose over time among young people who inject drugs. Efforts to address multiple central nervous system depressant use remain an important component of a comprehensive approach to overdose, particularly among young people.

Evaluation of poly-drug use in methadone-related fatalities using segmental hair analysis

In Denmark, fatal poisoning among drug addicts is often related to methadone. The primary mechanism contributing to fatal methadone overdose is respiratory depression. Concurrent use of other central nervous system (CNS) depressants is suggested to heighten the potential for fatal methadone toxicity. Reduced tolerance due to a short-time abstinence period is also proposed to determine a risk for fatal overdose. The primary aims of this study were to investigate if concurrent use of CNS depressants or reduced tolerance were significant risk factors in methadone-related fatalities using segmental hair analysis. The study included 99 methadone-related fatalities collected in Denmark from 2008 to 2011, where both blood and hair were available. The cases were divided into three subgroups based on the cause of death; methadone poisoning (N=64), poly-drug poisoning (N=28) or methadone poisoning combined with fatal diseases (N=7). No significant differences between methadone concentrations in the subgroups were obtained in both blood and hair. The methadone blood concentrations were highly variable (0.015–5.3, median: 0.52mg/kg) and mainly within the concentration range detected in living methadone users. In hair, methadone was detected in 97 fatalities with concentrations ranging from 0.061 to 211ng/mg (median: 11ng/mg). In the remaining two cases, methadone was detected in blood but absent in hair specimens, suggesting that these two subjects were methadone-naive users. Extensive poly-drug use was observed in all three subgroups, both recently and within the last months prior to death. Especially, concurrent use of multiple benzodiazepines was prevalent among the deceased followed by the abuse of morphine, codeine, amphetamine, cannabis, cocaine and ethanol. By including quantitative segmental hair analysis, additional information on poly-drug use was obtained. Especially, 6-acetylmorphine was detected more frequently in hair specimens, indicating that regular abuse of heroin was common among the deceased. In conclusion, continuous exposure of methadone provide by segmental hair analysis suggested that reduced tolerance of methadone was not a critical factor among methadone-related fatalities. In contrast, a high abundance of co-ingested CNS depressants suggested that adverse effects from drug-drug interactions were more important risk factors for fatal outcome in these deaths.

Concurrent Use of Alcohol and Sedatives Among Persons Prescribed Chronic Opioid Therapy: Prevalence and Risk Factors

Taking opioids with other central nervous system (CNS) depressants can increase risk of oversedation and respiratory depression. We used telephone survey and electronic health care data to assess the prevalence of, and risk factors for, concurrent use of alcohol and/or sedatives among 1,848 integrated care plan members who were prescribed chronic opioid therapy (COT) for chronic noncancer pain. Concurrent sedative use was defined by receiving sedatives for 45+ days of the 90 days preceding the interview; concurrent alcohol use was defined by consuming 2+ drinks within 2 hours of taking an opioid in the prior 2 weeks. Some analyses were stratified by substance use disorder (SUD) history (alcohol or drug). Among subjects with no SUD history, 29% concurrently used sedatives versus 39% of those with an SUD history. Rates of concurrent alcohol use were similar (12 to 13%) in the 2 substance use disorder strata. Predictors of concurrent sedative use included SUD history, female gender, depression, and taking opioids at higher doses and for more than 1 pain condition. Male gender was the only predictor of concurrent alcohol use. Concurrent use of CNS depressants was common among this sample of COT users regardless of substance use disorder status. PerspectiveRisks associated with concurrent use of CNS depressants are not restricted to COT users who abuse those substances. And, the increased risk of concurrently using CNS depressants is not restricted to opioid users with a prior SUD history. COT requires close monitoring, regardless of substance use disorder history.

Repeat DUI Offenders Who Have Had a Drug Diagnosis: Are They More Prone to Traffic Crashes and Violations?

Objective: Study objectives are to test for differences (1) in rates of negative traffic outcomes between DUI offenders who have lifetime drug use disorders (DUD) and those with no lifetime DUD; and (2) by drug class for those with a DUD. Methods: The study sample of 379 male and 74 female repeat DUI offenders was interviewed using the Composite International Diagnostic Interview. Results: Compared to those with an alcohol use disorder (AUD) only, the relative risk of being involved in a vehicular crash was greater for those with a central nervous system (CNS) depressant use disorder. The risk of being convicted of a traffic offense was higher for those with any DUD and for those with a CNS stimulant use disorder. Differences by class of drug used, after adjusting for demographics, were a 47 percent (confidence interval: 6–103%) greater risk of being in a crash with a CNS depressant use disorder and 28 percent (confidence interval: 11–48%) greater risk of a traffic conviction with a stimulant use disorder. Conclusions: Results underscore the increased risk of negative traffic outcomes among repeat DUI offenders diagnosed with DUD, particularly CNS depressant disorders, supporting the call to establish policies that include comprehensive evaluation and treatment for this population.

THE USE OF SUBLINGUAL BUPRENORPHINE–NALOXONE FOR REVERSING HEROIN OVERDOSE: A HIGH‐RISK STRATEGY THAT SHOULD NOT BE RECOMMENDED

We write with great concern regarding the recent report published in Addiction by Welsh and colleagues [1], and their suggestion that buprenorphine (alone or in combination with naloxone) may be a useful strategy in overdose reversal. While the details surrounding this case are consistent with a buprenorphine-precipitated reversal of heroin effects, there are a number of reasons why buprenorphine should not be recommended for overdose reversal and why such action may, in fact, contribute to increased overdose mortality. This is exemplified by a previous case in the literature of a person being administered intravenous buprenorphine in an attempt (unsuccessfully) to reverse a heroin overdose [2]. The authors of this paper note that this action may delay the initiation of proper life-saving actions, and we would concur that this is a grave concern. Welsh and colleagues are incorrect in suggesting that that there are no published cases of oral or sublingual buprenorphine-related overdoses. There is at least one published fatality following oral buprenorphine[3], and intravenous use of buprenorphine is not suspected in all fatalities [4]. The capacity for buprenorphine to reverse an overdose is probably limited to circumstances where the overdose follows the use of an opioid with low or moderate affinity (e.g. heroin, methadone, morphine) in an opioid-dependent individual (without reduced tolerance), and without recent use of other sedatives (alcohol, benzodiazepines). This represents a minority of fatal overdoses [5], as most overdoses are polydrug-related and occur following periods of reduced tolerance. Given the long half-life of many benzodiazepines, it is impossible for an ‘acquaintance’ to be sure what other drugs a person may have consumed in the previous 24 hours. The administration of buprenorphine to a person with recent central nervous system depressant use may contribute to respiratory depression and increase mortality risk. The principle is quite different to naloxone administration, which has no agonist opioid effects. In addition to this, the slow binding kinetics of buprenorphine suggest that a full response may not occur for up to half an hour [6], which is consistent with clinical experience that precipitated withdrawal does not occur immediately, with a time of onset of approximately 20 minutes. This is clearly too long to wait for a response in an overdose situation. Some consideration also needs to be given to the potential complications that may result from introducing a tablet into the mouth of an unconscious patient. This could result in inhalation and consequent respiratory complications. We feel it is irresponsible to suggest the use of buprenorphine (alone or in combination with naloxone) to reverse overdose in place of well-established life-saving procedures, such as training and application of basic first aid principles, calling an ambulance and, where available, subsequent administration of naloxone. We propose that great caution be exercised with regard to the suggestion that drugs that have not been evaluated for use in this way be administered in potentially fatal situations. Indeed, these issues raise ethical and medico-legal implications. One anecdotal report should be treated with extreme caution, and we do not agree with the conclusion that sublingually administered buprenorphine/naloxone might be recommended as a strategy to reverse opioid overdose. Nicholas Lintzeris and Suzanne Nielsen have conducted research funded by educational grants received from Reckitt-Benckiser (the manufacturer of Suboxone) and Nicholas Lintzeris has received consultancies from Schering Plough (distributors of Suboxone in Europe and Asia).

National Estimates of Exposure to Prescription Drugs with Addiction Potential in Community-Dwelling Elders

The use of prescription drugs with addiction potential is an overlooked and growing problem among today's elderly. This paper provides national prevalence estimates of exposure to prescription drugs with addiction potential among community-dwelling elders and explores risk factors for such exposure. Using the Medicare Current Beneficiary Survey, a nationally-representative database of Medicare eligibles, we calculated the prevalence of abusable prescription drug use, overall, by therapeutic class, and by drug. Nearly 22% (7.22 million) of all community-dwelling Medicare elders used at least one prescription medication with addiction potential. Opioid analgesics were used most frequently (14.9%; 95% CI 14.0, 15.8%); central nervous system (CNS) depressants were used by 10.4% of the nation's elders (95% CI 9.5,10.8%). Using logistic regression analysis, we examined the association of explanatory variables with three outcome variables: any controlled substances use, any opioid analgesic use, and any CNS depressant use. We found that females, whites, those aged 65–79, and those with non-spousal others, were significantly more likely to use one or more prescription drugs with addiction potential, controlling for health status and severity-of-illness. The significance and magnitude of several explanatory variables, including age, race, ethnicity, living arrangement, and health status, varied by therapeutic category. This paper provides an important first step in acknowledging the widespread use of abusable prescription drugs in elders, and provides a foundation for future research and practical solutions to preventing subsequent problem use of prescription drugs.