Psychopharmacology (2011) 218:471–481 DOI 10.1007/s00213-011-2349-6

ORIGINAL INVESTIGATION

Subjective, psychomotor, and physiological effects of oxycodone alone and in combination with ethanol in healthy volunteers James P. Zacny & Sandra Gutierrez

Received: 31 March 2011 / Accepted: 29 April 2011 / Published online: 21 May 2011 # Springer-Verlag 2011

Abstract Rationale Nonmedical use of prescription opioids is sometimes accompanied by the ingestion of ethanol. Whether ethanol increases the abuse liability-related effects of prescription opioids has not been determined. Objective The purpose of this study was to characterize the subjective, psychomotor, and physiological effects of oxycodone, a widely prescribed and abused opioid, and ethanol, alone and in combination. Methods Fourteen volunteers participated in a randomized, crossover trial in which they were exposed to placebo, oxycodone (10 mg), two doses of ethanol (0.3 and 0.6 g/kg), and oxycodone combined with the lower dose and the higher dose of ethanol on separate sessions. Results Several abuse liability-related subjective effects (drug liking, take again, pleasant bodily sensations) were not increased by the low dose of ethanol or oxycodone alone relative to placebo, but were when the two were combined. Self-reported liking of the higher dose of ethanol was higher than that of placebo, but oxycodone neither increased nor decreased this effect. Psychomotor and cognitive performance was not affected by any of the active drug conditions. Absorption of ethanol was decreased by oxycodone. Conclusions In this study, 10 mg of oral oxycodone combined with a low dose of ethanol generated abuse liability-related effects, but when tested separately, they did not. Further psychopharmacological investigations of this combination are warranted in light of these findings and the This research was supported in part by grant RO1 DA08573 from the National Institute on Drug Abuse. J. P. Zacny (*) : S. Gutierrez Department of Anesthesia and Critical Care MC4028, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA e-mail: [email protected]

fact that nonmedical use of prescription opioids is sometimes accompanied by use of ethanol. Keywords Ethanol . Prescription . Opioid . Healthy volunteer . Abuse liability . Subjective effects . Psychomotor . Drug interaction

Introduction Nonmedical use of prescription opioids (NMUPO) has been a major problem in the USA for over a decade, as evidenced by different national databases tracking prevalence of nonmedical use (Substance Abuse and Mental Health Services Administration 2010), and emergency room visits and drug abuse treatment center admissions associated with such use (Substance Abuse and Mental Health Services Administration 2009, 2011). There is evidence that NMUPO sometimes occurs in the context of alcohol use. In the 2008 Drug Abuse Warning Network (DAWN) survey, 32% of emergency department visits associated with abuse of hydrocodone also involved the use of alcohol and 25.1% of visits associated with oxycodone abuse involved the use of alcohol (Substance Abuse and Mental Health Services Administration 2011). Two recent surveys have examined the prevalence of use of prescription opioids and alcohol within the same day, and the results are consistent with the DAWN data. In one survey of undergraduates (n=4,580) at a large public Midwestern university in the USA, approximately 4% of undergraduates reported using prescription opioids at the same time they were using alcohol within the last year (McCabe et al. 2006). This was termed simultaneous use by the investigators. In another study which examined undergraduates (n=1,118) at a large mid-Atlantic university in the USA, 8% reported using alcohol and prescription

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opioids on the same day one or more times in the 6 months prior to the survey (Garnier et al. 2009). Whether the two drugs were used at the same time within the day could not be ascertained by the survey methods. There are few opioid–ethanol interaction studies in the literature that have focused on abuse liability-related effects, which is surprising given that the co-ingestion of the two drugs is not a rare event. In monkeys, in which a particular oral methadone dose did not function as a reinforcer, adding ethanol to that dose resulted in selfadministration of the combination at rates greater than water or ethanol alone (Shelton et al. 1998). In another study using a conditioned place preference paradigm, rats preferred a compartment in the chamber that had been paired with morphine and ethanol compared to a compartment that had been paired with only ethanol, only morphine, or only saline (Marglin et al. 1988). Although there have been several studies that have assessed effects of an opioid alone and in combination with ethanol on psychomotor/cognitive performance (Linnoila and Hakkinen 1973; Tedeschi et al. 1984; Girre et al. 1991), we are aware of only one study with human subjects that examined the co-ingestion of an oral opioid and ethanol with subjective effects being the primary endpoint. The opioid, hydromorphone, produced little effect by itself, and adding it to ethanol produced effects no different from ethanol alone (Rush 2001). It was suggested that the doses of the opioid tested were too low to adequately determine whether ethanol effects are increased by opioids. In the present study, we examined the subjective, psychomotor, and physiological effects of oxycodone, a widely prescribed and abused opioid, and ethanol, alone and in combination. We used a dose of oxycodone that in past studies has produced subjective effects (Zacny and Gutierrez 2003, 2008, 2009; Zacny and Lichtor 2008) and is in the upper range of therapeutically prescribed doses for relatively opioidnaïve patients, 10 mg. We tested two doses of ethanol (0.3 and 0.6 g/kg). Our primary hypothesis was that the two drugs taken together would produce a more positive profile than when either drug was taken alone and that the higher dose of ethanol combined with oxycodone would produce a greater magnitude of effect than the lower dose combined with the opioid. To more fully characterize the pharmacodynamics of the opioid–ethanol combination, we also included psychomotor testing and physiological measures into the study design.

Materials and methods Subjects The local Institutional Review Board approved the study. Prior to study participation, participants underwent a semistructured psychiatric interview and screening session in

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order to assess their drug use history and psychiatric and medical status for contraindications to study participation and in order to acclimate them to the tests and minimize any practice effects during experimental sessions. Qualifying subjects provided written informed consent. Twenty-seven subjects enrolled in the study; however, 13 subjects did not complete the study. Five subjects withdrew after completing one (four subjects) or two (one subject) sessions because of nausea and/or vomiting (all sessions involved administration of oxycodone and three of them also included alcohol). Another two subjects after one or two sessions withdrew because they disliked the taste of the beverage. Six participants did not complete the study for reasons unrelated to the study. Demographic data from the 14 participants who completed the study are presented in Table 1. All subjects had some history of recreational drug use, but none had histories indicative of substance abuse or dependence (American Psychiatric Association 2000). The two cigarette smokers reported smoking less than three cigarettes per week, and the two marijuana users reported smoking half a joint and one joint per week, respectively. In most cases, lifetime use of any one drug was less than 10 times, with the exception of cannabinoids—six volunteers reported using more than 50 times. Three subjects reported nonmedical opioid use in their lifetimes: two of the subjects reported use of opium (less than 10 times) and one subject Table 1 Demographic and substance use characteristics for study participants Characteristic Male/female (N) Age (years) BMI (kg/m2) Race White Black Current drug use Caffeine (beverages/week) Cigarettes (N) Alcohol (drinks/week) Marijuana (N) Lifetime recreational drug use (% ever used) Marijuana Stimulants Tranquilizers Hallucinogens Club drugs (ecstasy, ketamine) Inhalants Opiates

8/6 26.7±4.7 23.0±2.5 79% 21% 8.3±6.0 2 5.6±3.8 2 86% 50% 7% 43% 43% 7% 21%

Data are presented as N, mean±SD, or percent of participants

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reported nonmedical use of Vicodin (less than 10 times). Self-reported lifetime medical opioid use revealed that 12 volunteers used opioids (reported as Demerol or Meperidine, Morphine, Percocet or Percodan, Tylenol-3/Codeine, Vicodin or Lortab, and “opioids not listed above”). Lifetime drug use of each of these opioids was less than 50 times in any one person. Drugs and doses During separate sessions, participants received (1) placebo capsule with placebo beverage,(2) 10 mg oxycodone with placebo beverage, (3) 10 mg oxycodone with 0.3 g/kg ethanol beverage, (4) 10 mg oxycodone with 0.6 g/kg ethanol beverage, (5) placebo capsule with 0.3 g/kg ethanol beverage, and (6) placebo capsule with 0.6 g/kg ethanol beverage. The dose of oxycodone is at the high end of the clinically prescribed range in opiate-naïve individuals, but we chose this dose because a lower dose, 5 mg, yielded very few psychopharmacological effects (Zacny and Gutierrez 2008). The 0.3 and 0.6 g/kg ethanol doses are equivalent to 1.5 and 3 standard-sized drinks, respectively. For safety reasons, an initial two-session dose run-up pilot study (session 1: 10 mg oxycodone with 0.3 g/kg ethanol; session 2: 10 mg oxycodone with 0.6 g/kg ethanol) was performed with three volunteers prior to study initiation in order to determine (1) if cardiorespiratory measures were in a safe range and (2) if side effects were tolerable to the volunteers. Both safety criteria set forth in the dose run-up study were met, and the study was initiated. Oxycodone and placebo (lactose powder) were placed into opaque gelatin blinding capsules by an Investigational Drug Service pharmacist at the University of Chicago Hospitals. The ethanol and placebo beverages were prepared in the laboratory by a research technologist. The ethanol beverage was prepared with 95% ethanol, diet tonic water, and lime juice to make up a 6% (0.3 g/kg) and a 12% (0.6 g/kg) ethanol solution by volume. The placebo beverage contained the diet tonic water and lime juice mix with 1% ethanol (floated at the top of the beverage as a smell/taste mask to reduce expectancy effects). Beverages were presented in a volume of 560 ml for a 70-kg person with volume adjustments based on body weight, served in a Styrofoam cup, and consumed through a drinking straw. Oxycodone (or placebo) was administered 45 min prior to the ethanol (or placebo) drinking period so that the peak effects of oxycodone would be occurring close to the same time the blood alcohol levels were close to peaking. As determined from both pharmacokinetic and pharmacodynamics studies using oxycodone, we estimated peak effects of oxycodone to be approximately 60–120 min after ingestion (Poyhia et al. 1992; Mandema et al. 1996; Zacny and Gutierrez 2003; Walsh et al. 2008; Zacny and Lichtor

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2008; Cherrier et al. 2009) and peak ethanol effects to be approximately 15–30 min post-ingestion (Holdstock and de Wit 1998; King et al. 2002; Erblich et al. 2003). Design and procedures The study was a double-blind, double-dummy, randomized, placebo-controlled, crossover trial consisting of six sessions (at least 1 week apart) that took place in a departmental laboratory from 0800–1545 hours. Subjects were instructed to not eat food the morning of sessions or use any drugs (excluding normal amounts of caffeine and nicotine) 24 h prior to sessions. Upon arrival, breath alcohol, urine toxicology, and pregnancy (for females) tests were given, and subjects signed a form indicating that they had followed the food and drug restrictions. After signing the compliance form, subjects then ate, over a 20-min period, a light meal provided to them. The contents of the meal were selected by participants prior to study participation and were the same for all of their sessions (food items differed across subjects). A typical meal included a bagel with cream cheese, orange juice, a banana, and coffee. Forty-five minutes after the meal, baseline measures were assessed. At baseline, subjects completed several subjective effects forms and psychomotor tests, and their physiological status was assessed. After baseline measures were collected, subjects ingested a capsule containing oxycodone or lactose with 150 cc of water. Forty-five minutes later, subjects consumed another capsule (placebo) with 150 cc of water and then a beverage over a 13-min period (two 5-min drinking periods separated by a 3-min rest period). Subjects were told by the research technologist conducting the session that “the capsule they are about to ingest may or may not contain a drug” prior to each capsule administration and that “the beverage they are about to ingest may or may not contain a drug” prior to beverage administration. Mood, psychomotor/cognitive performance, and physiological measures were assessed throughout the session at prescribed time points for 300 min after capsule/beverage ingestion. Breath alcohol levels (BALs) were also measured at fixed time points for 300 min after the capsule/beverage ingestion. In an attempt to keep subjects blinded as to what the device measured, the technologist used a different breathalyzer (referred to as a “drug check monitor”) from the one used at the start of sessions. In order to keep the technologist conducting the sessions blinded, the breathalyzer’s display window remained covered throughout sessions and another person in the laboratory recorded the readings. After the session ended, participants were instructed not to engage in certain activities for the next 12 h (e.g., cooking, driving, using drugs), given questionnaires to complete at home 24 h after the session, and transported to

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(DEL/TA) questionnaire; a locally developed 20-item postsession sequelae questionnaire that assessed residual effects of the drug that subjects were asked to complete 24 h after each of the six sessions; and a variant of the MultipleChoice Procedure (MCP) (Griffiths et al. 1993). The DEL/ TA assessed the extent to which subjects currently felt a drug effect on a scale of 1 (I feel no effect from it at all) to 5 (I feel a very strong effect); assessed drug liking and disliking on a 100-mm line (0 mm=dislike a lot; 50 mm= neutral; 100 mm=like a lot); and assessed how much subjects “would want to take the drug(s) you received today again on another session, if given the opportunity” on a 100-mm line (0 mm=definitely would not; 50 mm=neutral (don't care); 100 mm=definitely would). Overall drug liking and overall wanting “to receive the drug(s) again” were also assessed at the end of each session and 24 h later on a modified version of the DEL/TA. The variant of the MCP required subjects to make a certain number of discrete choices between receiving the drug(s) again on another session, which was described to the subjects as hypothetical, and receiving or giving up varying amounts of money (ranging from $0 to $10). The maximum monetary value at which the subject chose drug(s) over money was referred to as the crossover value. Orderly data have been obtained with this variant of the MCP in other studies (Schmitz et al. 2003; Helmus et al. 2005). Subjects completed the modified MCP form 24 h following each session.

their home via a livery service. For safety reasons, subjects had to meet four criteria for discharge: be able to ambulate, have vital signs that were within 20% of their baseline values, have a breath alcohol level of ≤0.02% (NIAAA guidelines for home discharge), and be approved for discharge by the anesthetist. At least 24 h after the final experimental session, subjects completed a post-study packet of questionnaires, were debriefed, and received payment. Dependent measures The dependent measures were assessed before capsule/ beverage ingestion (baseline), as well as at fixed time points thereafter, e.g., after the first capsule ingestion and then at regular intervals after the subsequent capsule/beverage ingestion. Data used in the analysis included only those measures that were collected starting at 15–30 min after the capsule/beverage ingestion. Table 2 shows when the different dependent measures were collected. Those values that are bolded were included in the data analysis. Subjective effects Subjective effects were measured by six forms: a computerized, short form of the Addiction Research Center Inventory (ARCI) (Haertzen 1966; Martin et al. 1971); a locally developed 28-item visual analog scale (VAS); a locally developed 12-item opiate adjective rating scale (OARS) derived from two questionnaires sensitive to the somatic and subjective effects of opioids (Fraser et al. 1961; Preston et al. 1989); a Drug Effect/Drug Liking/Take Again

Psychomotor/cognitive performance Performance was measured with five tests: the Digit Symbol Substitution Test (DSST) (Wechsler 1958), a

Table 2 Timeline of events (minutes) BL 0 Oxycodone/placebo (PLC) capsule administration PLC capsule+onset of ethanol/placebo beverage period End of ethanol/placebo beverage period ARCI VAS OARS DEL/TA DSST ART, LRT, EHC Vital signs (HR, BP, RR, SaO2, MW) Miosis BAL

30 45 59 60 75 90 120 150 180 210 240 270 300 330 360

X X X X X X X X X X X

X

X

X

X X

X X

X X

X X

X

X X X X X X X X X

X X X

X

X X X X X X X X X

X X X

X

X X X X X X X X X

X X X

X X X X X X X X X

X X X

X X X X X X X X X

X X X X X

Xs in bold refer to values that were included in the statistical analysis of the data BL baseline, ARCI Addiction Research Center Inventory, OARS Opiate Adjective Rating Scale, VAS Visual Analog Scale, DEL/TA Drug Effect/Drug Liking/Take Again, DSST Digit Symbol Substitution Test, ART auditory reaction time, LRT logical reasoning test, EHC eye-hand coordination test, HR heart rate, BP blood pressure, RR respiration rate, SaO2 arterial oxygen saturation, MW Maddox Wing Test, BAL breath alcohol level

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Table 3 summarizes mean peak or mean trough values (±SEM) of subjective and physiological measures that were sensitive to one or more of the active drug conditions (relative to placebo).

“lightheaded,” and “sedated (calm, tranquil).” These effects of oxycodone were not altered significantly by either dose of ethanol (no significant differences between oxycodone alone vs. in combination with ethanol). There were six ratings in which ethanol alone at the 0.3 g/kg dose and oxycodone alone did not significantly affect ratings, but when combined differed significantly from placebo: ratings of “coasting (‘spaced out’), “difficulty concentrating,” “dreamy,” “floating,” “having pleasant bodily sensations,” and “in control of thoughts.” Ratings were significantly decreased with the latter measure and increased with the first five, compared to placebo. For OARS, oxycodone alone increased ratings of “skin itchy.” This effect of oxycodone was not altered significantly by either dose of ethanol (no significant differences between oxycodone alone vs. in combination with ethanol). In contrast, one or both doses of ethanol in combination with oxycodone significantly increased ratings of “dry mouth, “flushing,” and “nodding” relative to placebo, whereas oxycodone alone and ethanol alone did not. For DEL/TA, all active drug conditions increased “feel drug effect” ratings relative to placebo, but did not differ significantly from each other. A time course analysis on this measure did not provide evidence that subjects reported longer-lasting effects when ethanol was combined with oxycodone compared to oxycodone alone (Fig. 1). However, it should be noted that for the first 60 min after the capsule/beverage ingestion, ratings of “feel drug effect” were increased when ethanol was combined with oxycodone in an ethanol dose-related manner, relative to oxycodone alone. The differences though between the three conditions were not statistically significant. On both peak ratings of “like drug” and “take again,” the 0.3 g/kg dose of ethanol in combination with oxycodone significantly increased ratings relative to placebo whereas oxycodone and 0.3 g/kg ethanol alone did not (Fig. 2, top frames). Also, although oxycodone significantly decreased trough ratings of “like drug” and “take again” relative to placebo, when combined with either dose of ethanol it did not (Fig. 2, bottom frames). For Post-session Sequelae Questionnaire and variant of MCP, no active drug conditions differed significantly from placebo on measures collected in these questionnaires.

Subjective effects

Psychomotor performance

For ARCI, oxycodone alone increased scores of the LSD and PCAG scales. These effects of oxycodone were not altered significantly by either dose of ethanol (no significant differences between oxycodone alone vs. in combination with ethanol). Scores on the BG scale were not decreased by 0.3 g/kg ethanol alone or oxycodone alone, but were when the two substances were combined. For VAS, oxycodone increased ratings of “dizzy,” “high,”

On the five psychomotor/cognitive tests, there was no evidence of impairment in the active drug conditions compared to placebo.

logical reasoning test (Baddeley 1968), an eye-hand coordination test (Nuotto and Korttila 1991), an auditory reaction time test (Nuotto and Korttila 1991), and a locally developed recall memory test. Physiological measures Seven physiological measures were assessed: breath alcohol level, blood pressure, heart rate, arterial oxygen saturation, respiration rate, exophoria, and pupil size. Pupil size was measured with a commercial pupillometer (Neuroptics, San Clemente, CA). Statistical analyses Repeated-measures analysis of variance (ANOVA) was used for statistical treatment of the data (SigmaStat, Point Richmond, CA). The primary analysis compared peak (highest value obtained), trough (lowest value obtained), or mean effects of the six drug conditions. In the peak and trough analyses, only values collected beginning at the 15 or 30 min post-capsule/beverage administration time point (75 or 105 min after first capsule ingestion containing oxycodone or placebo) were included, and values were determined for each subject independent of time point. Mean effect analyses were done on those measures that were assessed only once either during or after experimental sessions. F values were considered significant for p≤0.05. When significance was achieved, the Holm–Sidak method for pairwise multiple comparison tests was done, comparing each of the five active drug conditions to placebo and, when appropriate, comparing one active drug condition to another. A secondary analysis measured time course of drug effects, but for the sake of brevity, only three measures will be presented in “Results.”

Results

Physiological effects Peak BALs were increased by ethanol in a dose-related manner, both alone and in combination with oxycodone.

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Psychopharmacology (2011) 218:471–481

Table 3 Mean peak or trough scores/ratings (±SEM) of subjective and physiological measures significantly affected by one or more of the active drug conditions P Value PLC Subjective measures ARCI BGa (range, 0–13) LSD (range, 0–14) PCAG (range, 0–15) Visual analog scale (range, 0–100) Coasting (“spaced out”) Difficulty concentrating Dizzy Down (depressed) Dreamy Drunk Floating Having pleasant bodily sensations High (drug “high”) In control of bodya In control of thoughtsa Lightheaded Sedated (calm, tranquil) Opiate adjective rating scale (range, Carefree Dry mouth Flushing Good mood Nodding Skin itchy Drug effect/drug liking/take again Feel drug (range, 1–5) Like drug (range, 0–100) Like druga (range, 0–100) Take again (range, 0–100) Take againa (range, 0–100) Physiological measures Blood pressure: diastolic (mmHg)a Exophoria (prism diopters) Heart rate (bpm) Heart rate (bpm)a Pupil size (mm)a Breath alcohol level (%)

<0.001 <0.001 <0.001

4.6 (0.4) 3.4 (0.4) 4.4 (0.8)

ETH 0.3

ETH 0.6

3.6 (0.6) 4.2 (0.6) 6.6 (0.8)*

2.7 (0.5)* 4.4 (0.5) 8.6 (1.0)* 33.5 39.1 8.2 7.9 29.4 32.1 25.4

(9.0)* (8.3)* (2.6) (3.9)* (7.6)* (9.2)* (8.9)

3.2 (0.6) 6.0 (0.7)* 7.9 (1.0)* 26.1 31.6 24.6 1.5 23.8 9.4 25.3

(8.2) (9.4) (9.3)* (0.9) (7.0) (4.4) (7.4)

OXY 10/ETH 0.3 OXY10/ETH 0.6

2.6 (0.6)* 5.5 (0.8)* 8.3 (1.0)* 35.7 42.4 18.4 4.4 28.6 17.9 26.7

(8.3)* (9.4)* (6.5) (2.9) (6.8)* (6.7) (7.6)*

2.9 (0.5)* 4.5 (0.6) 8.3 (0.7)*

<0.001 6.2 (3.1) 0.006 14.0 (5.5) 0.015 4.1 (2.8) 0.016 0.9 (0.3) 0.002 6.9 (2.3) <0.001 3.1 (2.5) 0.003 5.1 (2.8)

17.7 21.1 7.5 1.4 17.6 8.4 10.3

<0.001 23.3 (9.9) <0.001 6.8 (3.7)

24.4 (9.1) 12.2 (5.2)

43.7 (9.7)* 29.9 (8.1)*

37.0 (10.1) 26.6 (8.0) *

45.2 (8.4)* 34.6 (8.1)*

44.8 (10.2)* 31.6 (7.4)*

87.4 85.9 9.2 31.7

(5.1) (5.5) (2.6) (8.6)

75.6 76.1 27.8 42.3

(6.7)* (8.2)* (7.4)* (9.7)

84.3 86.3 32.9 50.1

(5.4) (5.5) (8.9)* (9.1)*

79.1 76.7 26.4 50.0

(5.7) (7.0)* (6.6)* (9.4)*

74.9 71.9 18.6 54.6

(8.2)* (9.0)* (5.0) (7.4)*

1.6 0.1 0.5 1.8 0.5 0.3

(0.3) (0.1) (0.2) (0.3) (0.3) (0.2)

2.2 0.6 0.6 2.9 1.3 0.4

(0.4)* (0.2) (0.2) (0.2)* (0.3) (0.2)

1.7 0.5 0.6 2.4 1.2 1.2

(0.4) (0.2) (0.2) (0.4) (0.4) (0.3)*

1.9 0.7 0.8 2.2 1.5 1.1

(0.3) (0.3) (0.2)* (0.3) (0.5)* (0.3)*

2.3 0.9 0.8 2.6 1.0 0.7

(0.4)* (0.3)* (0.2)* (0.3) (0.3) (0.2)

0.002 93.1 (4.2) <0.001 93.7 (3.8) <0.001 1.9 (0.6) 0.003 24.6 (9.2) 0–4) <0.001 1.2 (0.3) 0.005 0.1 (0.1) 0.009 0.1 (0.1) 0.005 1.9 (0.3) 0.011 0.3 (0.2) <0.001 0.1 (1.0)

(5.5) (6.6) (3.1) (0.5) (4.9) (4.2) (3.8)

OXY 10

35.3 34.2 8.1 1.3 31.0 24.1 28.6

(8.3)* (6.9) (2.9) (0.4) (8.0)* (7.3)* (7.9)*

<0.001 1.9 (0.2) <0.001 58.4 (3.2)

3.2 (0.2)* 62.1 (2.2)

3.6 (0.2)* 74.8 (5.2)*

3.4 (0.3)* 62.4 (5.7)

3.9 (0.2)* 73.0 (3.6)*

3.9 (0.2)* 71.9 (5.7)*

0.006 46.1 (1.2) <0.001 59.6 (3.2)

37.6 (3.8) 63.2 (2.6)

36.1 (3.7) 77.0 (5.9)*

27.8 (5.1)* 62.9 (5.4)

33.4 (5.6) 75.9 (4.2)*

38.4 (4.6) 73.9 (5.4)*

0.026 46.4 (2.9)

38.1 (4.2)

36.6 (4.2)

26.4 (5.3)*

37.4 (6.9)

41.9 (6.5)

<0.001 69.1 (1.5) 67.1 0.003 3.6 (1.1) 4.6 0.005 69.7 (1.4) 74.1 <0.001 57.3 (1.4) 63.0 <0.001 6.5 (0.3) 6.4 <0.001 – 0.038**

(1.7) 63.1 (1.2) 5.4 (2.6) 76.8 (2.2)* 65.1 (0.3) 6.3 (0.001) 0.081**

(2.3)* 64.6 (1.9) (1.1) 6.1 (1.1)* (2.6)* 68.3 (2.0) (2.3)* 57.2 (1.7) (0.3) 5.0 (0.3)* (0.005) –

65.7 5.4 71.6 61.1 5.3 0.028

(1.8) (1.0) (2.4) (2.0) (0.3)* (0.003)

61.6 6.3 72.1 60.1 5.0 0.063

(1.7)* (1.3)* (2.5) (1.8) (0.4)* (0.006)

PLC placebo, ETH 0.3 ethanol 0.3 g/kg, ETH 0.6 ethanol 0.6 g/kg, OXY oxycodone 10 mg a

Trough rating

*p<0.05, Holm–Sidak method for pairwise multiple comparison testing determined significant difference from placebo; **p<0.05, Holm–Sidak method for pairwise multiple comparison testing determined significant difference from identical ethanol dose when oxycodone was also given in session

Oxycodone significantly decreased peak BAL ratings at both the 0.3- and 0.6-g/kg dose. Thus, oxycodone altered systemic ethanol levels. A time course analysis revealed

that the differences occurred within the first 60 min after consumption of the alcoholic beverage (Fig. 3). Miosis, or pupil constriction, can be considered to be a proxy for

Psychopharmacology (2011) 218:471–481

Fig. 1 Time course of the effects of placebo (PLC: small square), 10 mg oxycodone (OXY: circle), 10 mg oxycodone and ethanol 0.3 g/ kg (OXY+ETH 0.3 g/kg: triangle), and 10 mg oxycodone and ethanol 0.6 g/kg (OXY+ETH 0.6 g/kg: large square) on the “Feel Drug Effect” question from the DEL/TA questionnaire. Each point is the mean across 14 subjects. The data which were included in the analysis included measures collected from 15 to 300 min after the capsule/ beverage administration. Solid symbols indicate a significant difference as determined by the Holm–Sidak method compared to the placebo condition for a given time point. For the sake of clarity, data from the two ethanol-alone conditions were omitted from the figure

blood oxycodone concentrations (Lalovic et al. 2006), so we could indirectly assess whether ethanol altered the pharmacokinetics of oxycodone. Trough values of pupil constriction were the same when oxycodone was ingested by itself or with ethanol. We also examined time course of pupil size when oxycodone was given alone vs. when it was given with ethanol. Figure 4 shows pupil size in the three oxycodone conditions as well as in the placebo condition. An ANOVA comparing the four conditions revealed that pupil size in all three oxycodone conditions at all testing time points were significantly smaller than in the placebo condition, but there were no differences in pupil size between the three oxycodone conditions, as determined by Holm–Sidak comparison testing. Ethanol or oxycodone alone or in combination had several other physiological effects, but there was no evidence of any interactions between the two drugs.

Discussion We hypothesized that the two drugs taken together would produce a more positive profile than when either drug was

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taken alone. This was found with the lower dose of ethanol: neither substance taken alone increased abuse liabilityrelated effects compared to placebo, but when the two were combined did indeed do so (increased ratings of “having pleasant bodily sensations,” drug liking, and “take again”). Also, oxycodone by itself produced ratings of dislike and a desire to not take the drug again if given the opportunity, but these ratings were no different than placebo when the opioid was combined with the lower dose of ethanol. There were several other subjective effects that were affected by oxycodone when combined with the lower dose of ethanol that were not evident when either substance was tested alone. We also hypothesized that the higher dose of ethanol combined with oxycodone would produce a greater magnitude of effect than the lower dose combined with the opioid, but this was not confirmed. Neither oxycodone nor ethanol, alone or together, impaired psychomotor or cognitive performance. The absorption of ethanol was decreased by oxycodone, but indirect evidence suggests that the pharmacokinetics of oxycodone were not affected by ethanol. The increased liking and other abuse liability-related effects when ethanol was combined with oxycodone are consistent with the epidemiologic data demonstrating that the co-use of opioids and ethanol occurs (McCabe et al. 2006; Garnier et al. 2009; Substance Abuse and Mental Health Services Administration 2011). However, abuse liability-related effects were not increased when oxycodone was combined with the higher dose of ethanol. In general, the higher dose of ethanol produced a number of rather robust subjective effects, but when oxycodone was combined with it, there was no further increase in effects. In addition, while there was a dose–response relationship with ethanol alone on a number of subjective effects measures, there was no such relationship when the two ethanol doses were tested with oxycodone. We do not have a ready explanation for this, in that it does not appear a ceiling effect was operating. A previous placebo-controlled study examined the effects of a therapeutic dose of hydromorphone with 0, 0.5, and 1 g/kg ethanol on subjective, psychomotor, and physiological measures (Rush 2001). Hydromorphone produced increased ratings on “like drug,” “concentration improved,” and “relaxed,” but these effects were not altered by ethanol. Therefore, unlike our study, opioid liking ratings were not increased by a lower dose of ethanol. However, in the Rush (2001) study, both doses of ethanol exceeded the lower dose of ethanol we tested in our study. It would be of interest to systematically replicate the Rush (2001) study with similar doses of ethanol that were used in the present study. It may be the case that ethanol combined with an opioid produces abuse liability-related effects to a greater extent than the opioid alone, but only when the dose of ethanol is low.

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Fig. 2 Peak ratings of drug liking (top left frame) and take again (top right frame) and trough (or minimum) ratings of drug liking (bottom left frame) and take again (bottom right frame) in the placebo (PLC), ethanol 0.3 g/kg (ETH 0.3), ethanol 0.6 g/kg (ETH 0.6), 10 mg oxycodone (OXY), 10 mg oxycodone and ethanol 0.3 g/kg (OXY+ETH 0.3), and 10 mg oxycodone and ethanol 0.6 g/kg (OXY+ETH 0.6) conditions. Asterisks indicate a significant difference from placebo as determined by the Holm–Sidak method. Brackets indicate SEMs. Ratings ranged on a scale of 0–100 (for liking: 0=dislike a lot, 50=neutral, 100=like a lot; for take again: 0=definitely would not, 50=neutral (don't care), 100=definitely would)

We did not detect psychomotor or cognitive impairment with oxycodone or ethanol alone or in combination. There could be at least two reasons for this, one being that the doses of the drugs assessed do not reliably produce impairment and the other being that the tests we used were insensitive in detecting drug-induced behavioral impairment. We have detected cognitive and psychomotor impairment with higher doses of ethanol and with oxycodone using the tests in this study (Thapar et al. 1995; Zacny and Lichtor 2008; Zacny and Gutierrez 2009). In addition, other studies in the literature while detecting decrements in performance with ethanol alone and/or opioids alone have failed to find a potentiated effect when the two drugs are combined (Linnoila and Hakkinen 1973; Tedeschi et al. 1984; Girre et al. 1991; Rush 2001). In a more recent study, a high dose of morphine (80 mg, approximately four to eight times a therapeutic dose) combined with 0.7 g/kg ethanol did not alter performance compared to morphine alone on a battery of psychomotor and cognitive tests in relatively opioid-naïve volunteers (Sokolowska et al. 2007). While one would have to think that at some point, a combination of ethanol and

opioids would produce greater impairment than either drug alone, the potential risks to subjects (e.g., significant cardiorespiratory depression) would preclude such a study from being done. Oxycodone lowered BALs, indicating that there was less absorption of ethanol into the bloodstream and the CNS relative to when ethanol was administered by itself. The degree of reduction was similar with both doses of ethanol, approximately 22%. Other studies have also documented such a finding. Both morphine and a peripherally acting mu opioid agonist, loperamide, reduced peak blood alcohol levels in rats (Linseman and Le 1997). Ethanol blood concentrations were approximately 20% lower following codeine pretreatment in healthy volunteers (Cudworth et al. 1975). In a study comparing effects of ethanol (adjusted for body mass) on simulated driving between non-drug-using healthy volunteers and patients maintained on methadone or levo-alpha-acetyl-methodol, the latter two groups had significantly lower BALs than the healthy volunteers (Lenne et al. 2003). The mechanism by which mu opioid agonists reduce ethanol absorption is thought to be via

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Fig. 3 Time course of the effects of ethanol 0.3 g/kg (ETH 0.3 g/kg: open square), 10 mg oxycodone and ethanol 0.3 g/kg (OXY+ETH 0.3 g/kg: solid square), 0.6 g/kg ethanol (ETH 0.6 g/kg: open circle), and 10 mg oxycodone and ethanol 0.6 g/kg (OXY+ETH 0.6 g/kg: solid circle) on breath alcohol levels (percent). Breath alcohol levels were measured from 15 to 300 min after the capsule/beverage administration. Asterisks below the solid symbols (i.e., OXY+ETH 0.3 or 0.6 g/kg) represent a significant difference from the corresponding open symbols (ETH 0.3 or 0.6 g/kg) at that time point

Fig. 4 Time course of the effects of placebo (PLC: small open circle), 10 mg oxycodone (OXY: solid triangle), 10 mg oxycodone and ethanol 0.3 g/kg (OXY+ETH 0.3 g/kg: solid square), and 10 mg oxycodone and ethanol 0.6 g/kg (OXY+ETH 0.6 g/kg: solid circle) on pupil size. Pupil size values were analyzed from 30 to 270 min after the capsule/beverage administration. The Holm–Sidak method revealed that at each of the testing time points, pupil size in each of the three oxycodone conditions differed significantly from placebo, but there were no differences in pupil size between the three oxycodone conditions

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opioid binding onto mu opiate receptors in the gastrointestinal tract, which reduces rate of stomach emptying and intestinal motility (Daniel et al. 1959; Burks 1973; Manara et al. 1986). Interestingly, however, other studies have not found such an effect—breath alcohol levels have not differed as a result of opioid pretreatment in several healthy volunteer studies, including pretreatment with propoxyphene, methadone, morphine, and hydromorphone (Cushman et al. 1978; Girre et al. 1991; Rush 2001; Sokolowska et al. 2007). One could posit that there is variation between mu agonist opioids in the degree to which they affect gastric motility, but many of the opioid studies that have documented the effect have used morphine as the test drug (Daniel et al. 1959; Manara et al. 1986; Yuan et al. 1996, 2002). We measured miosis in this study, and there is a high correlation between degree of miosis and plasma oxycodone concentrations (Lalovic et al. 2006). Miosis is considered to be a proxy for plasma oxycodone concentration (Lalovic et al. 2006), and using this measure, we did not find that oxycodone-induced miosis was altered by alcohol. This finding is consistent with three other studies showing lack of an effect of ethanol on opioid pharmacokinetics (Cushman et al. 1978; Ali et al. 1985; Sokolowska et al. 2007). However, two studies with propoxyphene have shown that plasma levels of this opioid increase when combined with ethanol, presumably because ethanol reduces first-pass metabolism (Sellers et al. 1985; Girre et al. 1991). In conclusion, our study provided some support for the hypothesis that oxycodone in combination with ethanol produces greater abuse liability-related subjective effects than either substance alone. The effect was confined, however, to the lower dose of ethanol and not to the higher dose, which had robust effects (including liking) in and of itself. There were other subjective effects that were increased by the low dose of ethanol combined with oxycodone relative to placebo that were not increased by either substance alone. Somewhat surprisingly, psychomotor and cognitive performance was unaffected by any active drug condition in the study. We probably would have detected impairment if we had tested higher doses of ethanol, but whether an opioid combined with a higher dose of ethanol would result in greater impairment is open to question as Rush (2001) and other researchers have not found such an effect (Linnoila and Hakkinen 1973; Tedeschi et al. 1984; Girre et al. 1991; Sokolowska et al. 2007). Regarding future studies, there are several avenues that could be explored. For example, the relationship between ethanol dose and the degree to which abuse liability-related effects of opioids are affected deserves to be examined more thoroughly. We only tested one dose of oxycodone—it would be interesting to test multiple doses of an opioid, as dose might be a crucial determinant in whether abuse liability-related effects of an opioid are

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increased by ethanol. Also, the reinforcing effects of a prescription opioid alone, and in combination with ethanol, could also be tested. In addition, ethanol–opioid studies could be conducted with prescription opioid abusers and light, moderate, and heavy drinkers to test the generality of the effects obtained in this study. Acknowledgments Research was supported in part by grant RO1 DA08573 from the National Institute on Drug Abuse. We thank Karin Kirulis for screening potential subjects and conducting the structured interviews and Jenny M. Jun for assistance in conducting the experimental sessions. Conflicts of interest The authors have no conflicts of interest to report.

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