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. Author manuscript; available in PMC: 2022 Feb 1.
Published in final edited form as: Psychopharmacology (Berl). 2020 Nov 9;238(2):539–549. doi: 10.1007/s00213-020-05702-w

Acute administration of oxycodone, alcohol and their combination on simulated driving - preliminary outcomes in healthy adults

Shanna Babalonis 1,2, Marion A Coe 2,3, Paul A Nuzzo 2, Michelle R Lofwall 1,2,5, Nur Ali 2, Paul A Sloan 4, Laura C Fanucchi 2,6, Sharon L Walsh 1,2,3,5
PMCID: PMC7855562  NIHMSID: NIHMS1645322  PMID: 33169203

Abstract

Rationale:

Epidemiological data indicate that drivers testing positive for an opioid drug are twice as likely to cause a fatal car crash; however, there are limited controlled data available.

Objectives:

The primary aim of this study was to assess the effects of a therapeutic dose range of oxycodone alone and in combination with alcohol on simulated driving performance.

Methods:

Healthy participants (n=10) completed this within-subject, double blind, placebo-controlled, randomized outpatient study. Six 7-hr sessions were completed during which oxycodone (0, 5, 10 mg, p.o.) was administered 30 min before alcohol (0, 0.8g/kg [15% less for women], p.o.) for a total of 6 test conditions. Driving assessments and participant-, observer-rated, psychomotor and physiological measures were collected in regular intervals before and after drug administration.

Results:

Oxycodone alone (5, 10 mg) did not produce any changes in driving outcomes or psychomotor task performance, relative to placebo (p> 0.05); however, 10 mg oxycodone produced increases in an array of subjective ratings, including sedation and impairment (p<0.05). Alcohol alone produced driving impairment (e.g., decreased lateral control) (p<0.05); however, oxycodone did not potentiate alcohol-related driving or subjective effects.

Conclusions:

These preliminary data suggest that acute doses of oxycodone (5, 10 mg) do not significantly impair acuity on laboratory-based simulated driving models; however, 10 mg oxycodone produced increases in self-reported outcomes that are not compatible with safe driving behavior (e.g., sedation, impairment). Additional controlled research is needed to determine how opioid misuse (higher doses; parenteral routes of administration), impacts driving risk.

Keywords: driving simulator, opioid, oxycodone, alcohol, ethanol, human, impairment, drugged driving

INTRODUCTION

The serious risks of driving under the influence of alcohol are well documented – data from 2018 indicate that 10,511 individuals in the United States died as a result of drunk driving (defined as a vehicle operator having a breath alcohol concentration of 0.08 and higher) (National Center for Statistics and Analysis, 2019). However, “drugged driving,” or driving under the influence of drugs (i.e., licit, illicit drugs, one drug or polysubstance use) is also a serious public health problem. The U.S. National Roadside Survey, a population sampling study of randomly selected on-road drivers last conducted in 2013-2014 (n=11,100; 85% of participants provided breath samples; 71% provided blood and/or oral fluid), found that 1.5% of evening/weekend drivers were over the legal alcohol limit (> 0.08%), 7.3% of drivers tested positive for medication (prescription or over-the-counter) with potentially impairing effects (e.g., stimulants, opioids, benzodiazepines) and 15.2% of drivers tested positive for an illicit drug (e.g., methamphetamine, heroin, cannabinoids) (Berning et al., 2015; Lacey et al., 2016). In the 2018 National Survey on Drug Use and Health, 20.5 million individuals ages 16 and older reported driving under the influence of alcohol in the past year, 12.6 million reported driving while intoxicated on illicit drugs and 6 million reported driving while under the influence of both alcohol and drugs (NSDUH, 2018). Further, the National Highway Traffic Safety Administration reported on the 2015 drug test results from fatally injured drivers who received post-mortem drug testing: 43.6% of fatally injured drivers tested positive for at least one drug – 16% of this sample tested positive for opioids; approximately half were positive for two or more drugs and 40% of the sample was positive for both alcohol and drugs. However, only 54% of deceased drivers received testing suggesting that these data underestimate the scope of the problem (Lacey et al., 2016; Hedlund and Macek, 2018).

Opioid analgesics are one of the most frequently prescribed medication classes, and prescription and non-medical opioids are widely misused. A meta-analysis examining data from several countries estimated that prescription opioid use increased the risk of vehicle crash involvement by a factor of 2.29 and increased the risk of crash culpability by 1.47 times (odds ratios; Chihuri and Li, 2017a). In regard to fatal vehicle crash culpability, one U.S. report indicated drivers testing positive for an opioid were two times more likely to cause a fatal crash than controls (2.18 odds ratio; Chihuri and Li, 2019), while higher estimates were reported in the European DRUID study, which reported a four-fold increase (4.07 odds ratio) (Bernhoft et al., 2012). Opioids are also frequently misused along with alcohol – data from the Centers for Disease Control and Prevention indicate that individuals who engage in binge drinking are twice as likely to misuse opioids, compared to non-drinkers (Esser et al., 2019). Alcohol use also potentiates the risk of fatal overdose from opioids (alcohol was involved in nearly 15% of opioid overdoses in 2017; [Tori et al., 2020]). Driving risk is also heightened when drivers use alcohol and opioids; for example, drivers responsible for fatal crashes involving two vehicles were more likely to test positive for opioids, alcohol or their combination compared to the non-culpable drivers involved in the crash (Chihuri and Li, 2019).

Despite the prevalence and enormous public health impact of opioid use, there are surprisingly few controlled studies that directly examine acute opioid effects or opioid/alcohol interaction effects on driving performance. To our knowledge, only three studies have examined the effects of acute opioid doses on driving outcomes in healthy participants who do not use drugs (Brown et al., 2018; Strand et al., 2019; Linnoila and Hakkinen, 1974). The first utilized a within-subject design (n=8) to examine the effects of hydrocodone (10 mg hydrocodone/325 acetaminophen, p.o.), alprazolam (1 mg, p.o.), and their combination (Brown et al., 2018). There were no significant changes in simulated driving performance produced by hydrocodone in comparison to placebo. However, significant impairment was observed after alprazolam, including increases in standard deviation of lane position (SDLP), an outcome indicating loss of lateral control of the vehicle (i.e., weaving in the lane), and increased lane departures (i.e., driving outside of the lane). Curiously, despite the findings with alprazolam alone, no effects were observed when alprazolam was given in combination with hydrocodone.

The second study also employed a within-subject design (n=22) to examine the effects of methadone (5, 10 mg, p,o.), buprenorphine (0.2, 0.4 mg, sublingual) and placebo on real-world highway driving performance in healthy participants with no current opioid use (Strand et al., 2019). The authors reported modest, yet significant changes in two outcomes: an increase in SDLP after 0.4 mg buprenorphine and changes in lane position (mean lateral location of vehicle in the lane, relative to the center) after both doses of buprenorphine. However, there were several instances in which drivers elected to stop before completing the drive due to sedation and not feeling safe to continue, suggesting that some drug-related impairment may not have been captured in the data. Cognitive and psychomotor task performance across several domains was impaired after administration of the highest doses of buprenorphine (0.4 mg) and methadone (10 mg).

The oldest study was a between-group design (n=10/group) that examined a moderate dose of codeine (50 mg, p.o.), alcohol (0.5 g/kg) and their combination on performance on a first-generation driving simulator model compared to two negative control groups - double-dummy placebo group and no drug/placebo administration group (Linnoila and Hakkinen, 1974). There were seemingly no effects of codeine, alcohol or their combination when compared to placebo (although these comparisons were not explicitly reported in the manuscript). When compared to the group receiving nothing (i.e., no placebo agents), codeine alone and alcohol alone increased collision frequency and instances of driving off the road, while codeine + alcohol did not further impair performance.

Given the limited data and absence of well-controlled studies regarding opioids and alcohol-opioid combinations and high rates of opioid and alcohol co-use, it is necessary to examine carefully the potential impairing effects of these substances on simulated driving performance. The current study examined the effects of 1) a therapeutic dose range of oxycodone (5, 10 mg), a prototypical opioid analgesic that is commonly prescribed and is commonly misused, 2) a dose of alcohol, which is known to impair driving ability and produces a peak breath alcohol concentration ≥ 0.08%, 3) oxycodone in combination with alcohol, and 4) placebo. Along with simulated driving performance measures (primary outcome), an array of physiological, subject- and observer-rated and psychomotor performance measures were also collected.

METHODS

Participants

Participants were healthy adults, ages 21-50 (≥ 21 years required due to state regulations surrounding alcohol administration) with BMI ≤ 30. All participants completed in-person screening evaluations that included substance use and psychiatric assessments, medical history and physical exam, blood chemistry, urinalysis, and ECG. Additional inclusion criteria included: no opioid misuse in the past 60 days, no current opioid use disorder and testing negative for opioids at each visit; drinking alcohol ≤ 12 days out of the 30-days prior to enrollment (confirmed through timeline follow-back), no current moderate-to-severe alcohol use disorder, lifetime history of drinking to impairment/intoxication; valid driver’s license and daily or near-daily driving experience. Participants provided observed urine samples during each screening visit – repeated positives (e.g., opioids, cocaine) were exclusionary. Other exclusion criteria included current physiological drug dependence requiring medical intervention (e.g., benzodiazepines), pregnancy, significant medical (e.g., seizure disorder) or psychiatric problems requiring medication or that would interfere with data collection (e.g., bipolar disorder) and inability to tolerate the simulated driving environment. All participants provided sober, written informed consent prior to participation and were paid for their participation. The study was approved by the University of Kentucky Institutional Review Board and was conducted in accordance with the Helsinki guidelines for ethical research.

Drugs

Doses were prepared by the University of Kentucky (UK) Investigational Drug Service. Commercially available doses of immediate-release oxycodone hydrochloride tablets (5 mg; Mallinckrodt Inc., Hazelwood, MO) were used; one or two tablets were over-encapsulated with a single gelatin capsule (Health Care Logistics, Circleville, OH) to create the doses (5, 10 mg oxycodone). Lactose monohydrate powder (Medisca Pharmaceuticals, Plattsburgh, NY) was used for the placebo condition and as filler in the active dose capsules. Alcohol doses were based on body weight. The alcohol solution contained USP grade ethanol (Everclear®; 0.8 g/kg, 15% less for women) and juice mixer; each drink was approximately 460 mL/70 kg (15% less for women) in volume with a standardized concentration of 16% alcohol. Placebo drinks contained juice with 1% alcohol. The oral solution was split into three aliquots contained in an opaque, covered cup with a straw; participants were required to drink each aliquot in 5 min (15 min total for full dose) (Kirkpatrick and de Wit, 2013).

Drug Selection Rationale

The doses of oxycodone (5, 10 mg oxycodone) are approximate starting doses for acute pain treatment (American Pain Society Guidelines, 2016). The alcohol dosing procedures (0.8g/kg, 15% less for women; administered across 15 min) produce a peak breath alcohol concentration (BrAC) approximately 0.08% - 0.09% (Kirkpatrick and de Wit, 2013; King etal., 2011; 2014; 2019), which is greater than or equal to the legal limit for operating vehicles in many jurisdictions. Oxycodone was administered 30 min prior to the start of alcohol (a 15-min dosing procedure) to align their peak behavioral effects (acute oral oxycodone administration: time to peak subjective effects ≃1 hr [Babalonis et al., 2013]; Tmax of oxycodone in plasma = 1.1(±0.1) hr; 2015]; similar alcohol administration protocols: time to peak subjective effects ≃ 15 minutes after drink completion; Tmax of alcohol in breath = approx. 15 min – 45 min after drink completion [King et al., 2011; 2014; Kirkpatrick and de Wit, 2013]).

Study Design

This study utilized a within subject, randomized, double-blind, double-dummy, placebo-controlled crossover design to assess the effects of 6 oral dose conditions: 1) placebo alcohol + placebo oxycodone; 2) placebo alcohol + 5 mg oxycodone; 3) placebo alcohol + 10 mg oxycodone; 4) alcohol + placebo oxycodone; 5) alcohol + 5 mg oxycodone; 6) alcohol + 10 mg oxycodone. Each participant completed 6 outpatient sessions (~7 hr/session) with at least 48 hr between sessions.

General Methods

After medical clearance, participants completed one practice session (4 hrs) to become familiarized with the driving simulator, questionnaires and assessments. At the start of each experimental session, participants were provided with a light, standardized breakfast (including either one standardized cup of tea or coffee for regular caffeine users) to be completed 0.75 hr prior to drug administration. Observed urine samples were collected and were tested for drugs of misuse, including methadone, oxycodone and semi-synthetic opioids, morphine-derived opioids, buprenorphine, cocaine, THC, amphetamine, methamphetamine and benzodiazepines and barbiturates (Discover™ Drug Test Card; American Screening LLC, Shreveport, LA) and for pregnancy in female subjects (hCG Test Card; Teco Diagnostics, Anaheim, CA); breath samples were also obtained and tested for the presence of alcohol AlcoMate Premium AL7000, Advance Safety Devices LLC, Chatswort, CA). If any samples tested positive for drugs or alcohol, sessions were cancelled.

Data were collected for 6-hr post oxycodone administration and subjects remained at the laboratory for at least 30 min post-session fora meal and continued observation. Before discharge, participants were required to have a BrAC ≤ 0.020 and successfully complete a field sobriety test. Free transportation (e.g., Uber, taxi) was provided to and from the laboratory for each session as driving was prohibited.

Physiological Measures and Breath Alcohol Concentrations

Heart rate, blood pressure, oxygen saturation (Dinamap Non-Invasive Patient Monitor, GE Medical Systems, Tampa, FL), expired end-tidal carbon dioxide (EtCO2), and respiration rate (N-85 Capnograph, Nellcor, Boulder, CO) were collected at baseline and in 30-min increments for 6 hr post oxycodone administration. Pupil diameter (PLR-200, NeurOptics, Irvine, CA) and breath alcohol concentration (BrAC) were measured before opioid and alcohol administration and every 15 min for the first 1.5 hrs and every 30 min thereafter.

Driving Simulator Task

The National Advanced Driving Simulator MiniSim™ was used to complete a driving task at baseline and 1, 2, 3 and 5 hr after oxycodone administration. MiniSim™ operation required use of the steering wheel, brake and accelerator pedals; three screens displayed the simulated environment and one screen displayed the vehicle’s instrument panel. Each driving course was approximately 10 min in duration and included suburban and urban sections. Five sections were presented during each drive: 1) a highway straightaway portion that allowed for a discrete assessment of lane position; along with several standardized incursion events: 2) a lead car braking suddenly on the highway, 3) a vehicle pulling out unexpectedly in front of the driver, 4) a pedestrian walking into the street, and 5) a car parked poorly on the street forcing the driver to maneuver around it. Participants were instructed to follow the rules of the road (e.g., follow posted speed limit signs in the simulated environment, obey stop signs and traffic signals).

Primary driving outcomes included SDLP (standard deviation of lane position; i.e., lateral control) and speed standard deviation (longitudinal control). Additional measures included mean break force (lbs of pressure on the break pad), steering wheel variation (number of steering corrections), break latency (reaction time), lane departures, collisions, headway distance (distance between driver’s car and lead vehicle), throttle-break interval and break force. Driving outcomes were analyzed across the entire drive.

Subjective and Observer-Rated Measures

Subjective effects measures included a 5-item Visual Analog Scale (VAS; Walsh et al., 2008) that presented the following questions: “Do you feel any drug effect?”, “How high are you?”, “Does the drug have any good effects?”, “Does the drug have any bad effects?” and “How much do you like the drug effects?” These items were presented at baseline and regular intervals after oxycodone administration (15, 23, 45, 60, 90, 105 and 120 min; every 30 min thereafter). A 14-item biphasic alcohol effect scale (Martin et al., 1993) and 20-item participant-rated opioid adjective scale (Fraser et. al., 1961) were collected at baseline and in 60-min intervals after oxycodone. Trained research assistants rated observable opioid and alcohol effects at baseline and in 60-min intervals after oxycodone. A 4-item VAS was presented after each simulated drive and included the following questions: “Driving was difficult,” “Do you feel that you could drive safely in a real car right now?,” “I performed well on the driving simulator,” and “I drove within the posted speed limits.”

Psychomotor Performance Measures

Two performance measures were collected at baseline and at 60-min intervals after oxycodone administration: a 90-second computerized version of the Digit Symbol Substitution Task (DSST) and a circular lights task (Wayne Saccadic Fixator™), which presented randomly illuminated red lights; subjects were instructed to extinguish as many lights as possible during the 1-min task.

The SafeDrive application was collected after each drive (baseline, 1, 2, 3 and 5 hr after oxycodone administration). This tablet application consists of four tests: simple visual, simple auditory, complex visual and complex auditory assessments (Miceli et al., 2015).

Statistical Analyses

All measures were initially analyzed as raw time course data using a two-factor repeated measures model (drug condition, time) with an AR(1) covariance structure. Peak/trough scores and peak change from baseline scores were calculated for individual participants within each dose condition and analyzed in a one-factor model (drug condition). Holm-Bonferroni correction for multiple comparisons was applied. Tukey’s post-hoc tests were completed to determine if a single dose was different from placebo and if dose combinations were significantly different from their individual constituent doses. Means and SEMs are presented and all models were conducted with Proc Mixed in SAS 9.3 (Cary, NC) with significance at p < 0.05.

RESULTS

Forty-one participants were screened for the study, fourteen were enrolled, and two did not complete due to schedule conflicts. Twelve participants completed the study; however, data from two were not included in the analyses (driving simulator data were lost for one due to a software malfunction, and one vomited shortly after drug/alcohol administration on several occasions – review of BrAC data and other outcomes suggested that their doses were not absorbed). Thus, the data analysis included ten participants (6 female, 4 male; 9 Caucasian, 1 African American, all non-Hispanic); with a mean age of 28.5 (± 0.3) years and having 15.8 (± 0.2) years of education. All participants were non-smokers. In the 30 days prior to enrollment, participants reported mean of 6.7 (± 1.2) drinking days, 2.5 (± 0.7) drinks per drinking day, 4.2 ± (1.0) drinks per week and 17.0 (± 2.6) past-month drinks. Four participants met criteria for past-year mild-severity alcohol use disorder; 5 met criteria for lifetime alcohol use disorder (mild-severity [n=4]; moderate [n=1]). None of the participants reported opioid use or misuse in the past 60 days; none met criteria for past-year or lifetime opioid use disorder. Other past-30 day drug use included cannabis use (n=1; one instance of use). All participants provided urine samples negative for all drugs during screening and prior to all experimental sessions.

Driving Simulator Outcomes

Figure 1 displays mean peak change from baseline on SDLP. As expected, alcohol produced significant increases in SDLP relative to placebo (p<0.05). Oxycodone did not significantly increase SDLP. The drug/alcohol combinations (alcohol + 5 mg oxycodone; alcohol + 10 mg oxycodone) also produced impairment on this outcome (p<0.05); however, the magnitude of these effects was similar to alcohol alone.

FIGURE 1.

FIGURE 1.

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Mean peak change from baseline outcomes are displayed for standard deviation of lane position (SDLP) as a function of oxycodone dose (0, 5, 10 mg, p.o.) (x-axis) and alcohol dose (placebo; 0.8 g/kg, 15% less for women, p.o.) (line functions on graph). Filled symbols indicate the dose condition is significantly different from placebo (0 alcohol, 0 OXY) (p < 0.05, Tukey post-hoc).

As displayed in Table 1, alcohol alone also increased peak break force (i.e., slamming the breaks) and speed standard deviation (i.e., loss of longitudinal control) (p<0.05). Time course analyses detected a significant dose by time interaction on the number of steering corrections across the entire drive (F(20, 158) = 1.97, p<0.05); post-hoc testing indicated that oxycodone (10 mg) with alcohol increased corrections (p<0.05). There were several driving measures for which no significant effects were detected, including lane departures, collisions, break latency, and headway distance (data not displayed).

TABLE 1.

Peak/trough means for driving-related outcomes for which a main effect of dose was detected. All driving simulator measures were analyzed as peak maximum score (SDLP was analyzed as peak change from baseline); the two subjective VAS items were analyzed as trough or minimum scores. The values displayed are mean peak/trough scores and standard error of the mean for each of the dose conditions: oral oxycodone (OXY) 5 and 10 mg; oral alcohol (0.8 g/kg, 15% less for women) or placebo (labeled 0 alcohol). Bolded F values indicate a significant main effect of dose (p < 0.05); bolded mean values indicate the mean is significantly different from placebo (0 alcohol, 0 OXY) (p < 0.05, Tukey post-hoc).

Outcome Measure 0 OXY 0 OXY 5 OXY 10 OXY 5 OXY 10 OXY
F 0 ALCOHOL 0.8 g/kg ALCOHOL 0 ALCOHOL 0 ALCOHOL 0.8 g/kg ALCOHOL 0.8g/kg ALCOHOL
Driving Simulator Outcomes - Peak Effects
Whole Drive
 Mean Brake Force (lbs of force) 5.2 1.4 (0.2) 1.9 (0.4) 1.5 (0.3) 1.7 (0.3) 1.5 (0.3) 1.7 (0.3)
 Speed Standard Deviation 3.7 14.8 (0.4) 15.4 (0.4) 14.9 (0.3) 14.7 (0.2) 14.7 (0.4) 14.9 (0.3)
 SDLP – peak change from baseline (cm) 3.9 2.4 (1.6) 9.6 (1.8) 5.3 (1.2) 6.0 (1.7) 10.6 (1.7) 10.0 (3.0)
Subjective Ratings of Driving Performance
Visual Analog Scale
 Could Drive a Real Car Safely (trough) 9.8 81.4 (9.0) 21.2 (10.8) 58.5 (13.6) 34.3 (14.4) 27.1 (10.2) 23.4 (10.5)
 Driving a Real Car Would be Difficult 4.3 6.9 (4.6) 32.7 (10.7) 15.4 (6.8) 46.6 (13.0) 30.7 (10.6) 45.9 (13.8)
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Subjective Ratings of Driving Performance and Impairment

Figure 2 (Panel A) displays trough ratings of the VAS question, “Could you safely drive a real car right now?” (lower values indicating less confidence in driving ability). Oxycodone produced significant dose-related decreases, with 10 mg producing effects similar in magnitude to alcohol (p<0.05) and oxycodone (5 & 10 mg) with alcohol (p<0.05). Panel B displays peak ratings of the Sedation Sub-Scale from the bi-phasic alcohol effects assessment. Ratings were significantly increased (relative to placebo) with 10 mg oxycodone (10 mg) and oxycodone (10 mg) with alcohol (p<0.05). Panel C displays peak ratings of the VAS question “How impaired do you feel?” Oxycodone (10 mg) produced significant effects (p<0.05) comparable to alcohol and oxycodone (5 &10 mg) with alcohol (p<0.05). Similar effects were detected on “Driving a real car would be difficult right now” (Table 1) with oxycodone (10 mg) (p<.05) and oxycodone (10 mg) with alcohol producing increased effects relative to placebo (p<0.05).

FIGURE 2.

FIGURE 2.

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Mean ratings are displayed for VAS trough ratings of “Could you safely drive a car right now?” (rating scale anchors: 0= not at all to 100 = definitely) (Panel A), peak ratings of Sedated from the bi-phasic alcohol questionnaire (likert-type scale from 0-10) (Panel B), and peak VAS ratings of “How impaired do you feel?” (rating scale anchors: 0= not at all to 100 = extremely) (Panel C). Values are displayed as a function of dose condition (n=10; ±1 SEM); oxycodone doses (mg) are displayed on the x-axis and the doses of alcohol are displayed as the two-line functions: circle = placebo alcohol, square = active alcohol (0.8 g/kg, 15% less for women, p.o.). The filled symbols indicate a significant difference from the placebo condition (Tukey post-hoc, p<0.05). Time course analyses detected a significant dose x time interaction for ratings of driving safely (F (20, 180) = 3.2, p<.05); a main effect of dose for ratings of sedated F (5, 45) = 2.5, p<.05); and a dose x time interaction for ratings of impaired (F (75,671) = 4.3, p<.05).

Psychomotor Effects

Alcohol significantly decreased the number of correctly completed trials on the DSST (p<0.05), with lower scores being indicative of impairment (i.e., slower response time or decreased accuracy). However, no other test conditions produced significant changes in psychomotor performance outcomes including the Circular Lights test and SafeDrive app (p>0.05).

Subjective Ratings of Drug Effects

VAS ratings of global drug/alcohol effects from baseline across the 6 hr of data collection are displayed as a function of oxycodone dose (individual panels) and alcohol pre-treatment dose (line functions within each panel) in Figure 3. As displayed in Panel A, alcohol produced significant increases in ratings for approximately 75 min relative to placebo (p<0.05). As seen in Panel B, the effects of oxycodone (5 mg) were placebo-like; however, when combined with alcohol, the effects increased comparable to alcohol alone (p<0.05). In Panel C, oxycodone (10 mg) produced significant increases for approximately 30 min (p<0.05); ratings increased further when combined with alcohol (p<0.05) with a similar time course and magnitude of alcohol alone and alcohol + oxycodone (5 mg).

FIGURE 3.

FIGURE 3.

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Mean time course effects are displayed for VAS ratings of “Do you feel any drug of alcohol effects right now?” (rating scale anchors: 0= not at all to 100 = extremely) The data are displayed as a function of dose: 0 mg oxycodone in Panel A, 5 mg oxycodone in Panel B, and 10 mg oxycodone in Panel C; the doses of alcohol are displayed as the two line functions: circle = placebo alcohol, square = active alcohol 0.8 g/kg, 15% less for women, p.o.). The filled symbols indicate a significant difference from the placebo condition at a given timepoint (Tukey post-hoc, p<0.05). Triangle symbols on the x-axis denote the time of each of the driving assessments (baseline and 1, 2, 3 and 5 hr post oxycodone dose). Time course analyses detected a significant dose x time interaction: (F (75, 671) = 6.2, p<.0001).

Alcohol and oxycodone effects were detected on peak ratings on an array of subjective and observer-rated outcomes, as displayed in Table 2. For example, alcohol alone increased scores on subjective measures, including drug liking, feeling drunk and increased the total score and on the bi-phasic alcohol questionnaire and observer-rated outcomes of drug effects (p<0.05). Oxycodone (5 mg) alone was largely placebo-like, while oxycodone (10 mg) alone increased ratings of bad drug effects, prototypical opioid effects assessed by the opioid adjectives measure and the sedation sub-scale of the alcohol questionnaire (p<0.05). The drug combinations (oxycodone 5 & 10 with alcohol) increased ratings significantly for several subjective and observer-rated outcomes (p<0.05); these were generally of similar magnitude to those of alcohol and oxycodone (10 mg) alone with no evidence of additive drug effects (Table 2).

TABLE 2.

Peak/trough means are displayed for physiological, subject- and observer-rated outcomes for which a main effect of dose was detected. All measures were analyzed as peak maximum score, with the exception of pupil diameter, oxygen saturation, circular lights and DSST outcomes (which are trough or minimum scores). The values displayed are mean peak/trough scores and standard error of the mean for each of the dose conditions: oral oxycodone (OXY) 5 and 10 mg; oral alcohol (0.8 g/kg, 15% less for women) or placebo (labeled 0 alcohol). Bolded F values indicate a significant main effect of dose (p < 0.05); bolded mean values indicate the mean is significantly different from placebo (0 alcohol, 0 OXY) (p < 0.05, Tukey post-hoc).

Outcome Measure 0 OXY 0 OXY 5 OXY 10 OXY 5 OXY 10 OXY
F (5,45) 0 ALCOHOL 0.8g/kg ALCOHOL 0 ALCOHOL 0 ALCOHOL 0.8g/kg ALCOHOL 0.8g/kg ALCOHOL
Physiological Measures
 Pupils 57.7 5.5 (0.3) 5.4 (0.2) 4.3 (0.3) 3.4 (0.2) 4.5 (0.3) 3.3 (0.2)
 EtCO2 4.22 35.3 (0.6) 35.6 (0.5) 36.0 (0.6) 37.1 (0.7) 36.1 (0.5) 37.5 (0.8)
Performance Measures
 DSST – Number Correct 3.6 36.6 (1.9) 31.5 (1.8) 36.3 (1.4) 33.8 (1.6) 33 (2.2) 33.2 (1.3)
Subject-Rated Measures
Drug Visual Analog Scales
 Overall Drug/Alcohol Effect 13.4 13.2 (4.0) 64.8 (7.5) 24.9 (7.2) 54.7 (12.7) 64.3 (7.0) 67.3 (7.7)
 Bad Drug Effect 4.5 3.3 (1.7) 23.6 (8.1) 6.6 (3.0) 43 (14.3) 19.7 (8.1) 34.6 (8.1)
 Like Drug Effect 5.1 9.0 (5.7) 40.3 (11.2) 15.3 (6.6) 29.4 (9.6) 37.5 (6.0) 46.6 (10.6)
 Drunk 30.9 3.5 (1.9) 63.1 (7.4) 1.2 (0.8) 9.4 (5.7) 54.7 (7.7) 55.7 (6.4)
 Impaired 12.4 9.4 (3.6) 59.2 (6.6) 18.3 (6.1) 49.2 (13.5) 58.2 (9.6) 62.5 (9.2)
Opioid Adjectives
 Total Score 7.9 8.1 (2.3) 17.2 (3.0) 10.0 (2.1) 15.8 (2.4) 16.3 (3.0) 18.5 (2.8)
Biphasic Alcohol Questionnaire
 Total Score 5.0 12.0 (5.3) 26.2 (6.6) 14.8 (5.2) 24.7 (5.6) 19.5 (5.9) 30.3 (7.0)
 Sedated Subscale 5.4 4.6 (1.5) 7.9 (2.5) 7.8 (1.9) 18.6 (4.9) 10.5 (2.9) 17.6 (4.6)
Observer-Rated Effect
Observer Adjectives
 Total Score 8.2 5.6 (1.1) 17.3 (3.3) 7.4 (0.9) 12.4 (2.3) 12.6 (1.1) 15.2 (2.6)
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Breath Alcohol Concentrations

Mean breath alcohol concentrations (BrAC) were elevated immediately after alcohol administration: (BrAC = 0.107% [± 0.006]) and gradually decreased to 0.017% [± 0.002] at 5.5 hrs after alcohol administration) (F (5,45) = 20.19, p<0.05). The mean BrAC for each of the post-dose driving assessments (collapsed across oxycodone condition; active alcohol conditions only): first drive = 0.088% [± 0.007]; second drive = 0.078% [± 0.003]; third drive = 0.062% [± 0.002]; fourth drive = 0.033% [± 0.002]). Oxycodone (5, 10 mg) did not alter the time course of or maximum BrAC (p>0.05).

Physiological Drug Effects

Oxycodone (5, 10 mg) dose-dependently decreased pupil diameter and 10 mg dose increased EtCO2 concentration (p<0.05; Table 2) - these effects emerged at 45 min post-dose, with comparable miosis occurring throughout 60 – 180 min (which corresponds to the first three driving assessment periods); decreases in pupil diameter (10 mg oxycodone) were observed through 6 hr post dose (F (5,45) = 9.75, p<0.001). Alcohol did not alter pupil diameter or EtCO2 concentration and did not change the time course or the magnitude of oxycodone effects on these outcomes (p>0.05; peak effects displayed in Table 2).

DISCUSSION

This study examined the effects of oxycodone (5, 10 mg), alcohol and their combination on simulated driving performance and subjective, psychomotor and physiological outcomes in a sample of healthy participants. These preliminary data indicate that oxycodone alone (5, 10 mg) did not significantly alter driving performance on any outcome measure, including the primary index of impaired driving, SDLP, and did not impair psychomotor performance. However, oxycodone alone (10 mg, but not 5 mg) significantly increased ratings related to sedation, impairment, and lack of concentration and decreased ratings of driving ability, an unfavorable array of effects that are incongruous with safe driving behavior. Alcohol alone significantly increased SDLP and impaired psychomotor performance. However, there were no indicatons on any outcome that the alcohol/oxycodone combinations produced greater effects than alcohol alone or oxycodone (10 mg) alone (i.e., no drug additivity).

There is a rich body of literature demonstrating alcohol effects on driving performance, particularly increases in SDLP and speed standard deviation, as demonstrated here. Increases in these two measures occur in both real world and simulated driving environments (e.g., Yadav and Velaga, 2019; Jongen et al., 2016). A meta-analysis of simulated driving outcomes indicated that on average, alcohol increases SDLP by 4 ± 0.5 cm and standard deviation of speed by 0.38 ± 0.1 km/hr (equivalent to 0.24 mph) (Irwin et al., 2017) – comparable to the effects reported here (peak SDLP: placebo = 2.4 ± 1.6 cm, alcohol = 9.6 ± 1.8 cm; peak speed standard deviation: placebo = 14.8 ± 0.4 mph, alcohol = 15.4 ± 0.4 mph).

Oxycodone alone, however, did not significantly alter driving performance on any outcome measure; for example, there were no oxycodone-related changes in SDLP or speed outcomes (p>0.05). Combinations of oxycodone (5, 10 mg) and alcohol produced significant increases in SDLP (p<0.05); however, the magnitude of these effects (SDLP, low dose combination: 10.6 [± 1.7]; high dose combination: 10.0 [± 3.0] cm) were similar to those produced by alcohol alone (9.6 [± 1.8] cm), suggesting that alcohol alone was sufficient to impair driving in this model and the addition of oxycodone did not enhance alcohol-induced impairment. Alcohol alone also decreased acuity on the psychomotor performance tasks (often used as proxies for driving performance), but oxycodone alone did not, which is consistent with other studies examining relatively low doses of opioids (e.g., review of opioid effects on driving-related outcomes by Strand et al., 2017). However, 10 mg of oxycodone produced effects on participants’ perception on their fitness to drive, including low confidence that they could safely operate a real car. These effects were similar to those produced by active alcohol. The 10 mg dose of oxycodone also increased participant ratings of feeling impaired (Fig. 2), as well as a number of other sedative-like effects that can be dangerous for driving (e.g., subjective and observer-rated opioid agonist effects, such as nodding, difficulty concentrating). It is not entirely clear why oxycodone did not alter driving behavior – it is possible that participants over-estimated the impact that sedation/impairment had on their driving ability, as they had little to no experience receiving opioid drugs or perhaps sedation occurred without motoric impairment. It is also possible that the driving simulator technology is not sensitive enough to detect opioid-induced changes in driving acuity within this dose range. Two studies have reported that acute opioid administration (also in healthy, non-drug using participants) did not impair simulated driving behavior when compared to placebo-control conditions (Brown et al., 2018; Linnoila and Hakkinen, 1974). However, one study of real world highway driving reported a small, yet statistically significant increase in SDLP (approx. 1 cm) with a low dose of sublingual buprenorphine (SDLP: placebo = 18.31 [±0.34]; 0.4 mg buprenorphine = 19.45 [±0.36]); but no changes with the other opioid doses tested (0.2 mg buprenorphine, 5, 10 mg oral methadone ) (Strand et al., 2019). Both buprenorphine doses produced minor changes in mean lane position (p<.05), but none of the doses changed speed outcomes. However, there were a total of six occasions in which participants stopped their vehicles due to feeling unsafe to drive: 0.4 mg buprenorphine [n=2], 10 mg methadone [n=1], 0.2 mg buprenorphine [n=1], placebo [n=1], which suggests some impaired driving may not have been captured in the data. In addition, cognitive and psychomotor task performance across several domains was impaired after administration buprenorphine (0.2, 0.4 mg) and methadone (10 mg). Several factors could account for the differing results reported by Strand and colleagues (2018): 1) the study tested on-road driving performance – this model is more sensitive to drug effects relative to simulated driving (Jongen et al., 2016); 2) the length of the drive – participants drove 100 km (62 miles), which may have challenged acute driving endurance, compared to the current study: five discrete driving trials of approx. 10.8 km (6.7 miles) each; 3) the number of participants enrolled, given the within-subject design (n=22) likely allowed for greater statistical power, compared to the current study (n=10) (and others: Brown et al., 2018 [n=8]; Linnoila and Hakkinen, 1974 [n=10/group]); and 4) the drugs and doses tested (e.g., short-acting vs. longer acting opioids). In addition to the small sample size, additional limitations to the current study include lack of 1) oxycodone pharmacokinetic outcomes (i.e., time course of oxycodone plasma concentrations; although see Babalonis et al., 2015), 2) outcomes collected on ascending limb of the alcohol exposure curve (all driving measures and nearly all other measures in the current study were collected on the descending limb), and 3) lack of generalizability to individuals with different drug and alcohol use patterns, as this study enrolled social/occasional alcohol drinkers without opioid use disorder – these limitations should be addressed by future studies.

The current data also indicate that alcohol-related decreases in driving acuity were not potentiated by opioid administration. Controlled driving studies have reported analogous findings - two studies administering agents that impaired performance (ketamine, alprazolam), reported that the addition of an acute opioid dose (fentanyl, hydrocodone) did not further increase driving impairment (Hayley et al., 2019; Brown et al., 2018). Similarly, no drug additivity was detected on participant ratings, psychomotor, or physiological effects in the current study (e.g., Table 2, Figures 2, 3). However, at least three other studies have examined the effects of a wide range of alcohol/opioid dose combinations on pharmacodynamic outcomes – all have reported that, across an array of outcomes, no potentiation occurred with the drug combinations, including subjective and psychomotor effects (Rush, 2001: 0.5, 1 g/kg alcohol and 1,2 mg hydromorphone; Zacny and Gutierrez, 2011: 0.3, 0.6 g/kg alcohol and 10 mg oxycodone; Setnik et al., 2014: 0.7 g/kg alcohol, 50, 80 mg morphine), safety (e.g., end tidal carbon dioxide) or pharmacokinetic outcomes (Setnik et al., 2014). However, additional studies testing higher doses and different participant samples (e.g., chronic opioid users) are required to determine the generalizability of these effects.

To date, little research has been conducted on the effects of chronic opioid dosing on driving; however, the available data generally suggest no detectable opioid impairment. For example, studies enrolling patient populations who are prescribed daily doses of opioid agonist medications (e.g., chronic pain patients taking opioid analgesics; patients maintained on opioid agonist medications for opioid use disorder) report that administration of daily opioid medications do not appear to impact simulated driving performance (Lenne et al., 2003; Nilsen et al., 2011; Galski et al., 2000) and meta-analyses on the effects of chronic use in pain patients report similar findings (Ferreira et al., 2018; Kress and Kraft, 2005); however, these studies caution against broad generalizability and specific circumstances that can potentiate risk (e.g., driving after recent dose escalation; combining opioids with benzodiazepines). Taken together, it is not clear how these studies and the current data align with the epidemiological reports, which suggest at least a two-fold increase in fatal car crashes when the driver tests positive for opioids – with the leading cause of the opioid-related crashes being due to failure to keep inside the lane (Chihuri and Li, 2019), which should be readily detected in the simulated driving environment. It is possible that relatively low, acute doses do not produce measurable levels of impairment – one limitation to the population-based crash data is that the driver’s opioid dose is unknown (rather, only opioid positive/negative status is known). Similarly, the interval between opioid dose administration and the car crash is also unknown, and it is possible that some opioid-positive tests are due to the presence of residual metabolites (indicative of previous use). It is also possible that the driving simulator cannot fully recreate certain features of real-world driving that increase crash risk (e.g., distractions from cell phones or passengers, complicated right-of-way decisions) or are not sensitive enough to detect the changes associated with opioid-related impairment. Nonetheless, there is also a large gap in the literature that could potentially address some of these discrepancies – there are no controlled studies that have examined high doses of opioids in individuals who misuse opioids. Opioid-related crashes have increased alongside the surges in the U.S. opioid crisis – in 1995, prescription opioids were detected in 1.0% of fatally injured drivers, this number rose to 7.2% in 2015 (Chihuri and Li, 2017b), suggesting opioid misuse as one likely contributing factor. Future studies should assess a wide range of opioid doses (e.g., heroin, fentanyl) and routes of administration (e.g., intranasal, intravenous) to determine if these dose conditions increase crash risk shortly after use. Overall, additional research needs to be conducted to determine how opioid use (acute vs. chronic use; misuse at higher doses) impacts driving outcomes.

Acknowledgments

Grants from the National Institute on Drug Abuse (R56 DA036635 [SLW]) and the National Center for Advancing of Translational Sciences (KL2TR000116-04 [SB]; UL1TR001998 [UK CTSA]). We thank Dr. Samy-Claude Elayi for patient support, the UK Investigational Pharmacy for preparing study medication, and the staff at the University of Kentucky (UK) Center on Drug and Alcohol Research for research support: Victoria Vessels, Emily Greene, Lindy Howe and Russell Lewis.

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Conflicts of Interest: The authors have no conflicts of interest to declare related to this project.

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