NIH - Alcohol and Other Drug Interactions: Unintentional Injuries and Overdoses: Epidemiology and Prevention (R01, R03, R21 - Clinical Trial Optional)

The following description was taken from the R01 version of this FOA.

The purpose of this funding announcement (FOA) issued by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH) is to encourage research grant applications that explore whether and how alcohol and other illicit drugs or illicitly used prescription drugs interact to contribute to unintentional injuries and poisonings as well as violent behavior and suicide and how to prevent and/or reduce simultaneous use of alcohol and drugs and their consequences.

Prevalence of Simultaneous Alcohol and Drug Use

Simultaneous alcohol and other drug use is a common phenomenon. A latent class analysis of data from the Monitoring the Future study of high school seniors surveyed from 1976-2016 (N=84,805; average response rate=83%) identified the following in the past 12 months.

Heavier simultaneous alcohol (binge 5+ drinks) and marijuana (SAM) use (11.29%)
Lighter SAM use (21.6%)
Concurrent alcohol and marijuana use (10.7%)
Alcohol-only use (56.4%)

Compared to concurrent alcohol and marijuana users and alcohol-only users, heavy SAM users were more often white and male, had parents with some college education, had lower grades (C+ or lower), more frequent evenings out with friends, truancy, illicit drug use other than marijuana, and a lower likelihood of college attendance, and membership. SAM use was lower in the most recent cohorts (2006-2011), compared with the 1986-1995 and 1996-2005 cohorts. The study did not explore whether the heavy SAM users were more likely to be drivers after drinking in motor vehicle crashes after drinking, particularly crashes resulting in injury or experience overdoses from alcohol or drugs only or the two in combination. This clearly warrants exploration.

Background:

Alcohol misuse is the third leading cause of death in the United States, contributing to over 88,000 deaths annually from 2006-2010 and nearly $250 billion in annual costs in 2010 to the nation (over $750 per man, woman, and child). Of these deaths annually, 49,544 are injuries and poisonings, many of which are among young people (nearly 16,500 below age 35). Disproportionately common among young people, injury and poisoning deaths produce twice the number of preventable years of life lost as chronic disease alcohol attributable deaths. Annually, there are 130 million emergency department (ED) visits. In 2014, 4,976,136 involved alcohol, a 47% increase per 100,000 population since 2006, and those ED visits cost $8.7 million.

Alcohol can increase the risk of injury (e.g. by slowing the decision-making process, reducing visual acuity, increasing reaction time, depressing the cough reflex (increasing risk of choking and aspiration), impairing postural control, balance and gait, reducing the capacity swim and resist cold temperature, and increasing the odds of falling asleep while smoking and or failing to hear a smoke alarm. By increasing confidence, inhibiting self control, and impairing assessment of risk, alcohol may also indirectly increase the risk of injury and the likelihood that conflicts will escalate into violence. A case crossover study in which patients served as their own controls showed a nine-fold increase in the odds of injury among patients who reported consuming 5-6 drinks during a six-hour period before the injury and a 17-fold increase among patients consuming 7 or more drinks. One case control emergency department study found significantly elevated odds of injury in 10 of 11 body regions for all types of injury among women who consumed 4 or more drinks and men 5 or more drinks the preceding 24 hours, controlling for age.

The most common types of acute deaths attributable to alcohol misuse and possibly alcohol in combination with drugs are traffic crash deaths, poisoning/overdose deaths, violent behavior, homicides, and suicides, resulting in a total of 49,000 deaths annually. We will focus on those types of events for illustrative purposes, but many of the same etiologic and prevention strategy questions may apply to other types of unintentional injuries (e.g., falls, drownings, or burns).

Applicants who are interested in assignment to and funding by the National Institute on Drug Abuse (NIDA) should consult the “2016-2020 NIDA Strategic Plan” ( https://www.drugabuse.gov/about-nida/2016-2020-nida-strategic-plan) to verify that their research aims align with the Objectives and the Priority Focus Areas that NIDA is emphasizing.

Traffic Crashes

Traffic crashes have long been the predominant type of alcohol-attributable injury death. A review of over 100 laboratory studies found that impairment in the skills needed to safely operate a motor vehicle begins with any departure from 0% blood alcohol content (BAC). Virtually all drivers exhibit impairment on some critical driving measure at 0.08% BAC. Deficits included reduced peripheral vision, poor recovery from glare, poor performance in complex visual tracking and reduced divided attention performance. Driver simulation and road course studies reveal poor parking and driving performance at low speeds and road risk observational studies have identified increased deterioration of speeding and braking performance.

In 2016, 12,514 people were killed in motor vehicle traffic crashes that involved any alcohol. That year, 10,497 died in alcohol-impaired traffic crashes where at least one motor vehicle operator had a BAC of 0.08% or higher. The most recent comparison of alcohol test result for drivers in single vehicle fatal crashes versus those stopped at random in national roadside research surveys found that, compared to sober drivers the same age at BACs of 0.02-0.05%, the relative risk of single vehicle driver crash death was 3.8, 2.4, and 3.3, respectively, for drivers ages 16-20, 21-34, and 35 or older. At BACs of 0.08% to 0.09%, the increased risks were 31.9, 23, and 20.9, respectively. At BACs of 0.15%, risks were 4728, 2171, and 1664.

In a 2007 national roadside survey, the National Highway Traffic Safety Administration collected both driver breath alcohol samples and saliva and blood samples for drugs. At night on weekends, the percent that tested positive for drugs was higher than for alcohol (14% versus 12%). In 2013, 17.7% drove after drug use and 8.3% drove after drinking. In 2012, according to the Fatality Analysis Reporting System of the National Highway Traffic Safety Administration, more than 70% of fatally injured drivers in 18 states were tested for both alcohol and drugs. In those states, of fatally injured drivers with known test results, 54% tested negative for both alcohol and drugs, 38% were positive for alcohol, and 36% for drugs. Sixteen percent tested positive for both alcohol and drugs. Of the fatally injured drivers with positive drug test results, 64% tested positive for marijuana and smaller percentages tested positive for stimulants, narcotics, depressants, or other drugs. Of course, a high prevalence of drugs in surveys or fatal crashes does not necessarily mean presence of these drugs increases traffic crash risk.

Reviews of case-control, culpability, and cohort studies of traffic risks posed by driving after using single illicit or medical drugs illicitly indicate significantly increased risk but less than risk posed by driving after drinking at blood alcohol concentrations of 0.08% or higher, the U.S. standard of driving while intoxicated. Results across studies of drug driving are less consistent than results on drinking and driving. Although a recent NHTSA case/control study of 3,000 crash and 6,000 control drivers did not find an increase in crash risk when driving after marijuana and other drug use, analyses did not focus on fatal and injury crashes, the types of crashes most likely to involve alcohol, nor did they focus on single vehicle crashes where the driver would be more likely to be at fault. Nor did analyses separately focus on young drivers under 21, who are most at-risk for alcohol-related crash involvement. NHTSA is funding a new case/control study with cases being drivers in injury and fatal crashes. Review studies show higher crash risk if drugs are used in combination. Five recent reviews report the highest crash risk when drugs are used in combination with alcohol. One review reported a significant two-fold increase in crash risk if someone drove after marijuana use. A meta-analysis of nine studies, reported a significant 2.1 increased fatal crash risk and a 1.9 overall crash risk if drivers drove after marijuana use. Another meta-analysis found higher risks for driving after drug use of amphetamines, benzodiazepines, and cocaine than after marijuana use. The relative risk of fatal crash if drivers drove after marijuana use was 1.25 and not statistically significant. However, among the studies rated of highest methodological quality, the risk was 7.0.

The most recent review of epidemiologic studies found statistically significant increases in traffic crash risk for benzodiazepines and z-hypnotics (in 25/28 studies), cannabis (in 23/36 studies), opioids (in 17/25 studies), cocaine (5/9 studies), amphetamines (in 8/10 studies), and anti-depressants (9/13 studies). Simultaneous use of multiple drugs yielded higher traffic crash risk, and the highest crash risks were linked to simultaneous alcohol and drug use.

The largest recent multi-national European study examined 2,490 seriously injured drivers and 1,112 killed drivers compared to control samples of 15,832 and 21,917 drivers stopped at roadside surveys in the same countries and tested for alcohol and drugs.

No significantly increased risk was found for drivers positive for marijuana but a slight but significant increase for injury crashes was observed. The increased odds ratios ranged from 1-3 medium increased risk (2 to 10) for injury or fatal crash risk was observed for cocaine, benzodiazepines, and medical opioids. High increased risk (5 to 30) was observed in drivers positive for amphetamines or other drugs used in combination. The highest increased risk (20 to 200) was for alcohol at BACs of 0.12% and higher and alcohol in combination with drugs.

One meta-analysis of over 120 studies found frequent users of marijuana (unless used in conjunction with alcohol show less impairment at the same dose either because of phsysiologic tolerance or learned compensating driving behavior. Nonetheless, the higher the blood THC concentration, the greater the driving impairment. Evidence from laboratory studies on cannabis indicate impairment persists for some weeks after cessation, raising the possibility that both tests for recent and long-term cannabis use may be needed to evaluate crash risk linked to cannabis use, alone, with other drugs, and with alcohol.

A review of experimental laboratory studies published between 1998-2015 found decrements in behaviors related to safe operation of motor vehicle vehicles associated with benzodiazepines, cannabis, cocaine, opioids, GHB (a sedative and anxiolytic drug), ketamine, stimulants, and antihistamines each increase risks for impairment. Low doses of stimulants did not seem to cause impairment. Simultaneous alcohol and drug use was not explored.

Most recently, case/control and case/crossover analyses of adult emergency department injured patients (N=2,804) found that alcohol significantly increased injury risk in both types of analyses. Risk of injury were not significantly increased for marijuana, stimulants, and depressants. Combined alcohol and marijuana use produced marginally significant increased risk and significant increased risk for alcohol in combination with two or more drugs simultaneously consumed.

Limitations in some of the above studies include:

Low response rates
Different measures for cases (blood) and control (oral fluids)
Small sample sizes and low statistical power
Variability in length of time after crash and drug test administration
Use of inactive metabolites of THC
Inability to measure mode of administration of cannabis (inhaled versus oral)
Lack of control for potential confounding factors

An expert panel convened by the National Highway Traffic Safety Administration recommend 1) pharmacology/toxicology reviews of drug effects, 2) standard behavioral assessment of drivers under the influence of drugs and alcohol, and 3) epidemiologic studies and reviews.

Examples of research that are encouraged by the FOA are given below and are not meant to be exclusive.

Specific Areas of Research Interest

Key unanswered questions are:

Does driving after alcohol and drug use increase fatal, injury, and property damage crash risk, and are the risks the same for each type of crash?
Do risks increase additively, synergistically, or less than additively?
With which drugs does combined alcohol and drug use independently increase risk?
Does crash risk of drug used in combination increase more for some drug combinations?
Is there an increased risk for use of alcohol and multiple drugs in combination relative to alcohol and individual drugs?
What percent of people killed in crashes involving drug-using drivers and drug-and-alcohol-using drivers are persons other than the drug-using and drug-and-alcohol-using drivers?
All the questions cited above need to assess whether risks vary by age, gender, race/ethnicity, BAC level, drug level, history of drug or alcohol dependence or both.

Various types of studies exploring drug use and driving alone or in combination with alcohol could be undertaken.

Etiology studies:
Experimental studies of impairment on tasks needed to operate a motor vehicle safely
Road course studies
Culpability studies
Case/control analyses
Longitudinal studies
Prevention studies:

Studies on the effects of change in drug laws or drug involvement alone or in combination with alcohol, such as the following:

Per se laws, which make it illegal to drive after any illicit drug or medicine used outside physician prescribed recommendations. Currently, only 17 states have drug per se laws, whereas all states have 0.08% blood alcohol per se legal limits.
Administrative license revocation laws allowing police to seize the license at the scene of any driver refusing a roadside drug test or who fails.
Laws requiring impaired driving offenders to be assessed for both alcohol and drug dependence and successful treatment completion requirements before driver license reinstatement.
Studies of changes in drinking and driving laws should also explore the effects of those laws on alcohol and drug involvement in various levels of traffic crashes. For this to be feasible, higher percentages of fatally injured drivers in crashes will need to be tested in most states.
Improvements in roadside survey methods and in specific roadside tests for drugs in particular are needed.

See the National Institute on Drug Abuse’s website for marijuana research priorities.

Intensive case studies of quasi-experimental community enforcement interventions will be needed to test which alcohol and drug driving enforcement strategies are most effective (e.g., publicized sobriety check points or saturation patrols).

Studies of multi-component community interventions studies are needed to assess what combination of enforcement, education, and treatment/counseling strategies are most effective, including publicity about risks of driving after drugs and alcohol in combination and highly publicized enforcement.

Combinations of speed and safety belt enforcement with alcohol and drug driving enforcement also need to be tested, and the impact of heightened speed enforcement, speed cameras, and safety belt checkpoints on reducing crash involvement of drivers using alcohol or drugs or both could be explored.

Alcohol and Overdoses

Overdoses

According to the Surgeon General (2016), in 2015 in the United States, 67 million people reported binge drinking, and 27 million used illegal drugs or misused prescription drugs. In 2016, there were over 60,000 drug overdose deaths.

Rates of overdose deaths have risen dramatically in the last three decades, primarily from sedatives and pain killers. Overdose fatalities now exceed traffic injury deaths. An estimated one in four of overdose deaths involve alcohol. Based on data from the Nationwide Inpatient Sample, a probability sample of community hospitals, 1.5 million patients were hospitalized in 2008 for an overdose, half of which involved alcohol. The acute toxic effects of alcohol are manifest in symptoms of alcohol poisoning, which include vomiting, slow and irregular breathing, hypothermia, and mental confusion.

Alcohol may play a more substantial role in overdoses attributed to other drugs. If people have co-occurring alcohol or drug problems, their judgment may be impaired, prompting them to take larger and potentially more lethal doses of alcohol or drugs. Alcohol pharmacologically interacts with a variety of illicit and prescription drugs, including opioids and related narcotic analgesics, sedatives, and tranquilizers. Also, BACs required for fatal overdose are lower when alcohol is combined with prescription drugs. ICD-9 codes require medical examiners and coroners to list drugs when present, which may prompt under-reporting of presence of alcohol relative to drugs when overdoses occur.

Specific Areas of Research Interest

Examples of research that are encouraged by this FOA are given below and are not meant to be exclusive:

In what states and cities are all overdose deaths routinely tested for both alcohol and drugs, and what are the percentage and types of overdose deaths that involve alcohol?
How can testing be increased in other cities/states?
Does the percent involving alcohol vary by type of drug either illicit or prescription drugs illicitly used?
Do these percentages vary by age, gender, and race/ethnicity?
What proportion of overdoses is unintentional, and does this vary by alcohol involvement?
How were drugs and alcohol involved in overdoses obtained?
What are the trends over time, and have there been greater increases in overdoses from drugs and alcohol in combination rather than drugs alone or alcohol alone?
What is the impact of various interventions to reduce overdoses, such as drug package informational inserts, prescription monitoring laws and registries?
What impact do various alcohol policies have on alcohol and drug-related overdoses (e.g., legal drinking age changes, changes in alcohol prices/taxes, outlet density, hours of sale, and monopoly versus privatized sales)?
What impact does recreational and medical marijuana legalization have on overdoses involving marijuana, other drugs, and alcohol. Has this increased the use of edibles and does that affect rates of overdose from alcohol and marijuana?
What impact do various drug driving laws have on drug overdose rates?
What is the impact of early age of drug and alcohol initiation on overdoses involving alcohol and drugs?

Violence

Alcohol and other drug (AOD) use in the commission of other-directed aggression and violent behavior

Survey research data often has found a strong relationship between alcohol use and the expression of violence including, for instance, physical assault. In addition, evidence from carefully controlled human laboratory research has increased understanding of how?and how much?alcohol consumption is related to displays of aggression in the laboratory. Several reviews have concluded that alcohol?s role in the expression of aggression, violence, and violent crime is best described as a causal one. In general, the experimental research has found that while alcohol consumption does not increase aggression for all persons and in all situations, it does tend to increase aggression for persons with specific traits, such as among those with lower levels of empathy and high dispositional aggressivity.

In the ?real? world, however, people who use alcohol often also use illicit or licit drugs and, sometimes such people engage in violent behavior. In recent years, study of the effects of alcohol and drug usage on intimate partner violence (IPV) has been conducted among patients in substance abuse treatment. Thus, one study found that the interaction of alcohol and cocaine use during the 90 days prior to treatment was associated with violence severity, a finding that was largely replicated in subsequent research by the same team. In addition, laboratory research conducted with social drinkers has found support for the hypothesis that alcohol is more likely to increase aggression in men who report higher, as opposed to lower, levels of past-year stimulant drug use,

Nevertheless, in cases of violence in which multiple substances may have been ingested, several methodological issues hamper a full understanding of which substance might be contributing to the violence. While human laboratory research holds the potential to clarify this matter, subjects in such experiments investigating, for instance, alcohol?s effects on aggression typically do not also ingest drugs as part of the experiment. As a result, little can be said with certainty about the effects of co-usage of alcohol and other drugs on violence expression. When alcohol and illicit drugs are used together, the observed effects would seem to depend on the particular substances involved. However, a review concluded that while alcohol clearly was the drug with the most evidence to support a direct intoxication-violence relationship, the literature concerning benzodiazepines, opiates, stimulants, and PCP suggested that personality factors were at least as important as pharmacological ones in explaining aggression. Moreover, some drugs appear to have varying effects at different doses.

Furthermore, since surveys that measure past violence victimization rarely measure whether a substance had been used by the perpetrator at the time of the violent event, the event-level contribution of substance use is difficult to determine from such an approach. Even when the survey instrument does investigate event-level substance use, most studies tend to focus on the correlates or outcomes of use of just one particular substance. However, the fact that use of any particular substance tends to be highly correlated with the use of other substances means that the effects on violence expression of alcohol, for example, often can be wrongly attributed to one of the other drugs ingested at the time of the event.

Approaches to prevention of alcohol- and drug-related violence

Some reductions in violence have been observed as a result of implementation of a range of environmental-, community-, family- and school-level alcohol prevention programs. However, in considering the effects of such interventions on involvement in violence among individuals who use both alcohol and drugs, a largely unexplored?but important?question is this: Does the AOD-using individual?s drug use level/frequency remain the same, or increase, or decrease following reductions in alcohol use? The research literature offers relatively few hints at an answer. Thus, a review that assessed the body of research on the effects of psychosocial?but not environmental?interventions for concurrent problem drinking and illicit drug users reported that no conclusions could be made regarding the relative effectiveness of different types of interventions owing to the paucity of data and low quality of the retrieved studies. A systematic review concluded that following treatment for illicit drug use, alcohol use may increase the patients? likelihood of relapsing to his/her primary drug of abuse, with a subgroup of such individuals possibly vulnerable to becoming primarily addicted to alcohol. In short, then, it is not clear that environmental-level?or even psychosocial prevention or treatment?interventions that are aimed at reducing alcohol use in concurrent AOD users will necessarily reduce or eliminate use of the other substance(s) being used by such individuals. To the extent that this reduction is not realized, it must be considered that the individual?s ongoing substance use is likely to continue to contribute to at least some expression of violence, although this clearly should be seen as an area ripe for future research.

Treatment of AOD users as violence prevention

Violent users of both alcohol and other drugs may have trouble remaining in or complying with substance use treatment regimens. For instance, in a study of alcohol dependent men?with and without concurrent illicit drug use?who had been arrested for IPV, randomly assigned to group behavioral therapies and followed for 12 weeks, concurrent AOD users attended significantly fewer treatment sessions, had significantly fewer percent days abstinence from alcohol use, and significantly more days of positive breathalyzer tests than did the alcohol-only users, as well as significantly more impairments in anger management styles. Thus, alcohol dependent men who continue to use illicit drugs may require additional interventions to effectively control their drug use and anger management.

Future research that uncovers prevention and treatment approaches with AOD-using individuals that show promise in also reducing intentional displays of violence is urgently needed.

Alcohol and other drug (AOD) use in attempted and completed suicides

During the last decade, suicide surpassed motor vehicle crashes as the leading cause of injury death in the United States. Suicide is the 10th leading cause of all deaths in the population as a whole and ranks higher among younger people. For instance, suicide is the third leading cause of death for adolescents ages 12-17 and young adults ages 18-24 and the second leading cause among those ages 25-34.

Alcohol and other drugs often play roles in attempted and completed suicides. An analysis of data from people aged 15-29 in European countries concluded that higher levels of alcohol use were associated with completed suicides. Data from more than 45,000 adolescents age 16 from 16 European countries revealed that teens who drink alcohol, use licit drugs, smoke marijuana or use other illicit drugs are more likely to attempt suicide. Further, odds ratios for attempting suicide approximately doubled with each additional drug used. During 2005-2007, 31% of U.S. suicides by multiple substance overdoses involved a mixture of alcohol and prescription drugs (National Center for Injury Prevention and Control. As for ED visits for drug-related suicide attempts, alcohol was involved in 11% of cases among adolescents and 30% among young adults in 2008 (SAMHSA, 2010bc). Numbers of ED visits for suicide attempts involving combined alcohol and drug use increased 51% for males of all ages and 15% for females of all ages from 2005-2009 (SAMHSA, 2011bc).

Using data from the Nationwide Inpatient Sample, a dataset comprised of roughly 8 million discharge records per year from a 20% sample of public hospitals across the country, a study examined the role of alcohol in hospitalizations for suicide-related drug poisonings (SRDP) in adolescents 12-17 and young adults 18-24 between 1999 and 2008. Among 12-17-year-olds, there were 14,615 hospitalizations for drug poisonings in 2008, 72% which were suicide-related. Among 18-24-year-olds, there were 32,471 hospitalizations for drug poisonings in 2008, 64% of which were suicide-related. Rates of SRDP stayed the same for adolescents and decreased for young adults across the decade. However, the percentage of SRDP involving a concomitant alcohol overdose increased for both age groups. Thus, the likelihood that an adolescent or young adult who attempts suicide via drug poisoning will also consume an excessive amount of alcohol during the event is on the increase.

In addition to substance use, suicide is associated with a range of psychiatric conditions. Patients suffering from obsessive-compulsive personality disorder, depression, anxiety disorders, PTSD, and other psychiatric conditions are at elevated risk for use and abuse of drugs and alcohol, and the addition of such substance abuse increases the odds of suicide attempts beyond the psychiatric conditions alone. The complicated interrelationships between psychiatric conditions, substance abuse, and suicide make it challenging for researchers to tease out the independent effects of substance use alone. Moreover, research suggests that many patients hospitalized for suicide attempts will make another attempt requiring hospitalization in the coming years, highlighting the importance of effectively treating the AOD use upon initial attempt.

Specific Areas of Research Interest

Pharmacologically, how does co-usage of alcohol and one or more of the various illicit drugs contribute to expressions of aggression and other- and self-directed violence, and to what extent is this association moderated by BAC phase, setting, and characteristics of the individual user?
Which of the various environmental-, community, and family-level approaches to alcohol prevention are the most effective in limiting expressions of other- and self-directed violence among individuals who use both alcohol and other drugs, and what are the mechanisms by which this reduction is realized?
How might drug-involved violence be influenced by physical proximity to alcohol outlets, and how might land use zoning approaches aimed at de-concentrating clusters of alcohol outlets affect frequency of drug-involved violence in adjacent blocks?
Does enrollment in alcohol treatment reduce frequency/severity of violence in those individuals who use both alcohol and other drugs, and if so, what are the mechanisms by which this reduction is realized?
For all prevention and treatment approaches mentioned above, are observed reductions in use of one substance (e.g., alcohol) accompanied by increases (i.e., substitution effect) in use of other substances (e.g., illicit drugs)?

Deadlines: standard dates and standard AIDS dates apply

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Filed Under: Funding Opportunities

NIH – Alcohol and Other Drug Interactions: Unintentional Injuries and Overdoses: Epidemiology and Prevention (R01, R03, R21 – Clinical Trial Optional)