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ORIGINAL INVESTIGATION

Intravenous oxycodone, hydrocodone, and morphine
in recreational opioid users: abuse potential
and relative potencies

William W. Stoops & Kevin W. Hatton &
Michelle R. Lofwall & Paul A. Nuzzo & Sharon L. Walsh

Received: 16 April 2010 /Accepted: 26 June 2010 /Published online: 28 July 2010
# Springer-Verlag 2010

Abstract
Rationale Nonmedical use and abuse of prescription
opioids is an increasing public health problem. Intravenous
(IV) administration of opioid analgesics intended for oral
use is not uncommon; yet, little is known about the relative
abuse potential of these drugs when administered intrave-
nously to recreational opioid abusers without physical
dependence.
Methods This inpatient study employed a double-blind,
randomized, within-subject, placebo-controlled design to
examine the relative abuse potential of IV doses of
oxycodone, hydrocodone, and morphine. Nine healthy
adult participants reporting recreational opioid use and
histories of IV opioid use completed 11 experimental

sessions, including one active-dose practice session. IV
doses were infused over 5 min and included three identical
doses of each opioid (5, 10, and 20 mg/10 ml) and saline
placebo. Physiological, subjective, and performance effects
were collected before and for 6 h after drug administration.
Results All three opioids produced prototypical mu agonist
effects (e.g., miosis; increased ratings of liking) that were
generally dose-related. Pharmacodynamic effects were
observed within 5 min of IV administration. Physiological
effects were more prolonged than subjective effects for all
three drugs. While the magnitude of effects was generally
comparable across drugs and qualitatively similar, valid
potency assays indicated the following potency relationship:
oxycodone > morphine > hydrocodone.
Conclusions There were modest potency differences
between oxycodone, hydrocodone, and morphine, but
their overall profile of effects was similar, indicating
significant abuse potential when administered intrave-
nously.

Keywords Oxycodone . Hydrocodone . Morphine .

Prescription opioids . Diversion . Abuse potential

Introduction

Illicit prescription opioid use is now more prevalent in the
USA than the use of cocaine, heroin, or methamphetamine.
Data from the 2008 National Survey on Drug Use and
Health indicate that 4.7 million individuals over the age
of 12 reported current nonmedical use of prescription
opioids, whereas 1.9 million, 200,000, and 314,000
people reported current cocaine, heroin, and metham-
phetamine use, respectively (Substance Abuse and Mental
Health Services Administration 2009). The majority of

W. W. Stoops (*) : M. R. Lofwall : P. A. Nuzzo: S. L. Walsh
Department of Behavioral Science, University of Kentucky
College of Medicine,
140 Medical Behavioral Science Building,
Lexington, KY 40536-0086, USA
e-mail: [email protected]

W. W. Stoops: M. R. Lofwall : S. L. Walsh
Center on Drug and Alcohol Research, University of Kentucky,
Lexington, KY, USA

W. W. Stoops
Department of Psychology, University of Kentucky College of
Arts and Sciences,
Lexington, KY, USA

K. W. Hatton
Department of Anesthesiology, University of Kentucky College of
Medicine,
Lexington, KY, USA

M. R. Lofwall : S. L. Walsh
Department of Psychiatry, University of Kentucky College of
Medicine,
Lexington, KY, USA

Psychopharmacology (2010) 212:193–203
DOI 10.1007/s00213-010-1942-4

prescription opioids are formulated for oral use, but they are
often taken intranasally or intravenously when misused
(Davis and Johnson 2008; Katz et al. 2008). Recent
epidemiological studies have estimated that up to 40% of
illicit prescription opioid users, including sporadic users,
have experience with intravenous injection of these drugs
(Havens et al. 2007; Hays et al. 2003; Katz et al. 2008;
Rosenblum et al. 2007). The purpose of this experiment was
to determine the abuse potential and relative potencies of
intravenous prescription opioids in recreational opioid users
with a history of intravenous injection of these drugs, a
population that is at increased risk for developing opioid
dependence.

While prescription opioid analgesics have been available
clinically for decades and the nonmedical use of these drugs
is increasingly recognized as a public health problem, only
recently has the relative abuse potential of these drugs been
examined using controlled laboratory methods in human
participants (Comer et al. 2008, 2009; Walsh et al. 2008;
Zacny 2003; Zacny et al. 2005; Zacny and Gutierrez 2003,
2008, 2009; Zacny and Lichtor 2008). Many of these
studies tested the effects of orally administered opioids
(Walsh et al. 2008; Zacny 2003; Zacny et al. 2005; Zacny
and Gutierrez 2003, 2008, 2009; Zacny and Lichtor 2008)
with results suggesting that oxycodone, hydrocodone, and
hydromorphone have comparable abuse potential. One
study has tested the effects of intravenously administered
prescription opioids in opioid-dependent participants
(Comer et al. 2008). As with oral dosing, the results of
that study demonstrated that intravenous administration of
oxycodone and fentanyl produced prototypical opioid-like
effects that were qualitatively similar to those of heroin
and suggest comparable abuse potential amongst the
agents.

The combined findings from previous studies serve to
demonstrate that a number of prescription opioids, when
administered orally or intravenously, produce qualitatively
similar behavioral and physiological effects across three
different populations (i.e., nondrug-abusers, recreational
opioid users, physically dependent heroin users), indicating
significant potential for abuse. However, given that these
drugs are taken intravenously by sporadic users (Havens et
al. 2007; Katz et al. 2008), it is important to determine the
effects of prescription opioids when administered by the
intravenous route to a nondependent population as this is
a common route of administration. Hydrocodone and
oxycodone were chosen as the test drugs in this study
because they are the first and second most commonly
prescribed opioids in the USA, respectively (IMS
National Prescription Audit PlusTM, see Walsh et al.
2008). Moreover, oxycodone and hydrocodone are both
full mu opioid receptor agonists that have been identified
as specifically contributing to the observed increase in

illicit prescription opioid use (Substance Abuse and
Mental Health Services Administration 2007). No study
to date has examined the abuse-related effects of intrave-
nous hydrocodone. Oxycodone is available in the USA in
combination products (i.e., with aspirin or acetaminophen)
and opioid-only formulations and is regulated under
Schedule II. Hydrocodone alone is regulated under
Schedule II but is presently marketed in the USA only in
combination products, which fall under the less tightly
regulated Schedule III designation. However, hydrocodone
is available as an opioid-only product outside of the USA (see
drug procurement information below). Morphine was selected
as the reference compound because it is also a full mu opioid
receptor agonist and has been extensively studied under
controlled laboratory conditions to determine abuse potential
and has historically been used in many studies as a positive
control test drug (e.g., Comer et al. 2008; Jasinski and Preston
1986; Teoh et al. 1993, 1994; Walker and Zacny 1999).

Methods

Participants

Participants were adult recreational opioid users who
reported a history of intravenous opioid use and were not
physically dependent on opioids at the time of the study
(see first section under “Results” for details). Participants
were recruited through local advertisements and were paid
for their participation. Individuals who were seeking
treatment for their substance abuse, or successfully
sustaining abstinence in the community were excluded.

All participants were determined to be in good health by
medical history and physical examination, an electrocardio-
gram, and laboratory tests. Participants were carefully
screened to eliminate those with seizure disorders, asthma or
other respiratory disorders, head injury, hypertension, cardio-
vascular disease, or abnormal ECG. All participants reported
illicit use of opioids, which was confirmed by urinalysis
during screening. This study was approved by the University
of Kentucky Institutional Review Board, and participants
gave their written informed consent prior to screening and
enrollment. The consent document stated that this study
would involve intravenous administration of opioid drugs. A
Certificate of Confidentiality was obtained from the National
Institute on Drug Abuse for the project, and the study was
conducted in accordance with the Helsinki guidelines for
ethical human research.

Participants enrolled as inpatients for approximately
4 weeks in this study. Sessions were conducted at least
48 h apart on weekdays (i.e., Monday, Wednesday, and
Friday). Prior to each session, urine specimens and
breathalyzer tests were obtained and tested for illicit drugs,

194 Psychopharmacology (2010) 212:193–203

including methadone, cocaine, THC, benzodiazepines,
morphine-derived opioids, amphetamine, barbiturates,
methamphetamine, phencyclidine, tricyclic antidepressants
(Multi-Drug Screen Test Dip Card 10 panel; American
Screen Corp., Shreveport, LA), oxycodone (Oxycodone
Dip Card; American Screen Corp., Shreveport, LA),
buprenorphine (Buprenorphine Test Card; American
Screening Corp., Shreveport, LA), and alcohol (AlcoHawk,
Q3 Innovations, Independence, IA) to ensure the absence of
recent use. Females were tested for pregnancy (HCG
Pregnancy Dip Card; American Screening Corp., Shreveport,
LA) during each screening visit and on the morning of each
session. Participants could not eat from midnight on the
day of a session but could smoke cigarettes up to 1 h
prior to session; they were not allowed to eat or smoke
throughout the duration of the experimental sessions.

Drugs

An existing Investigational New Drug Application from the
Food and Drug Administration was modified to support the
conduct of this study (#69,214). All study medications
were prepared in the Investigational Pharmacy at the
University of Kentucky. Commercial suppliers were used
to obtain intravenous solutions of oxycodone hydrochlo-
ride (10 mg/ml; Napp Pharmaceuticals, Cambridge, UK),
hydrocodone hydrochloride (15 mg/ml; Abbott GmbH &
Co, Ludwigshaffen, Germany), and morphine sulfate
(25 mg/ml; Amphistar Pharmaceuticals, South El Monte,
CA). These solutions were drawn into syringes and
diluted with saline to doses of 5, 10, and 20 mg/10 ml
for each drug. The 0 mg/10 ml condition (placebo) contained
only saline (Hospira, Lake Forest, IL). Each 10-ml dose was
infused using a syringe pump (MedFusion® 3500, Smiths
Medical, Keene, NH) into a catheter placed into a vein in the
participant’s nondominant arm under the supervision of an
anesthesiologist (KWH or his designee) over a period of
5 min. Dose order was random, with the exception that the
highest dose of any drug could not be given before a lower
dose had been tested.

Study design

A double-blind, within-subject, randomized, placebo-
controlled design was used. There were 11 sessions
conducted at the University of Kentucky Clinical Research
Development and Operations Center (CRDOC), a dedicated
inpatient research unit. The first session served as a practice
and safety session during which subjects received the
intermediate dose of morphine (10 mg/10 ml, IV) under
single-blind conditions (data are not reported from this
session). Participants then completed ten double-blind,
randomized, experimental test sessions in which they

received a single test drug. Baseline data were collected
for 30 min prior to drug administration at 9:00A.M. and data
collection proceeded for 6 h thereafter.

Experimental sessions

An intravenous catheter was placed into a vein in each
participant’s nondominant arm by CRDOC nursing staff
prior to the start of session for dosing and as a
precautionary measure to ensure immediate venous access
in the event of an emergency. The catheter was kept patent
by a saline drip during sessions. Study staff arrived at the
UK CRDOC at approximately 8:00A.M. on session days and
completed baseline measures with participants. Participants
were seated in a cushioned chair in their hospital room
directly in front of a Macintosh Mini using OSX (Apple
Computer, Cupertino, CA) that was used to collect the data.
The computer was programmed to record physiological
measures (except pupil diameter, expired carbon dioxide
(CO2) and respiratory rate) and to present questionnaires in
the appropriate order; participants entered their responses by
using a computer mouse and/or keypad. The research
assistant was seated behind the computer to initiate tasks
and complete observer-rated measures.

Physiological measures Oxygen saturation, blood pressure,
and heart rate were collected every minute using an
automatic monitoring device (Scholar III model 507ELC2,
Criticare Systems INC, Waukesha, WI). Pupil diameter was
determined from Polaroid camera photographs (Polaroid
Corp., Cambridge, MA) using a two-fold magnification
or a pupillometer (PLR-200, NeurOptics, Irvine, CA) in
constant room lighting. Pupil photos were used to
measure pupil diameter in two participants and, due to
a suspension of film manufacturing, the pupillometer was
used to measure pupil diameter in seven participants.
Expired CO2 (expressed in mm Hg) and respiratory rate
(in breaths/minute) were measured using a Capnograph
(N85, Nellcor, Boulder, CO).

Subject- and observer-rated measures Subject-rated mea-
surements included visual analog scales, the Addiction
Research Center Inventory (ARCI) short form (Martin et al.
1971) and a 17-item adjective checklist that encompassed
both an Agonist Scale and the Fraser Scale (see Walsh et al.
1995 for scale descriptions). An observer-rated opioid
adjective rating scale was also used (Walsh et al. 2008).
Table 1 outlines when physiological, subject- and observer-
rated performance measures were completed in each
session.

Eight visual analog scale items were used throughout
each session (six listed in Walsh et al. 2008, plus two
additional items: “Does the drug make you have UN-

Psychopharmacology (2010) 212:193–203 195

PLEASANT THOUGHTS?” and “Does the drug make you
have UNPLEASANT BODILY SENSATIONS?”). After
the continuous visual analog scale (i.e., eight items
recorded on a min-by-min basis for 20 min following the
start of dosing; see Table 1), participants answered four
additional questions each time they completed this measure:
“Does the drug make you feel IRRITATED?,” “Does the
drug make you feel DIZZY?,” “Does the drug make you
feel NAUSEATED?,” and “Does the drug make it
DIFFICULT TO CONCENTRATE?”

Ocular and performance tasks Three additional measures
were collected as outlined in Table 1, including two ocular
tasks sensitive to disruptions of perception and ocular
motor control and a computerized Digit Symbol Substitu-
tion Task (DSST; McLeod et al. 1982). These tasks were
included to measure potential perceptual and performance
effects of opioids. The ocular measures are sensitive to
perceptual disruptions produced by opioids (see Walsh et al.
2008) and are reported here as nadir CFF 1 and CFF 2 (in
Hz) for the Critical Flicker Fusion test and maximum
exophoria (in diopters) for the Maddox Wing test.

Statistical analysis

All measures collected during the experimental sessions
were analyzed initially as raw time course data using a two-
factor analysis of variance (ANOVA with Proc Mixed to
account for any missing data: drug condition × time). The
online physiological measures, collected on a min-by-min
basis during the experimental sessions, were averaged across
time to yield intervals ranging from 5 to 30 min, which
corresponded to the other physiological data collection.
Tukey’s post hoc tests for repeated measures were used to
compare scores following active doses to those observed
following placebo across time points. When a significant
interaction of dose condition and time was observed,

significant main effects are not reported. Outcomes are also
not reported for measures on which only a significant main
effect of time was observed.

In addition to the raw score analyses, peak scores (either
nadir or maximum depending upon the direction of effects)
for individuals were obtained for repeated measures
collected during the experimental sessions; these were
analyzed using 1-factor ANOVA with drug condition as
the factor. Tukey’s post hoc tests for repeated measures
were used to compare peak scores following active doses to
those observed following placebo.

Peak effect data from measures where significant main
effects of dose were observed were analyzed further
comparing oxycodone and hydrocodone to morphine using
the Finney (Finney 1964) method for parallel line bio-
assays. The analysis of parallel line bioassays is used to
determine the relative potency of two compounds. This
analysis was used to determine that the dose–response
functions (excluding placebo) of oxycodone, hydrocodone,
and morphine did not differ with respect to shape and slope
(i.e., no significant differences in linearity and parallelism,
respectively) and showed slopes significantly different from
0 (i.e., significant regression) without differences in
magnitude of effect across drugs (i.e., no significant
differences in preparation). Six-point bioassays were used
for all measures (three doses per drug), log doses were
employed and morphine served as the reference compound
in the estimates. Data from all measures meeting these
criteria were used to calculate relative potency estimates
and 95% confidence intervals for those estimates.

Results

Participants

Nineteen participants were screened for the study. Three
completed an initial dose ranging pilot study in which the

Table 1 Data collection schedule during experimental sessions

BL 0 5 10 15 20 25 30 35 50 65 80 95 110 125 155 185 215 245 275 305 335 365

Recorded Continuously Throughout the Session

Minutes

Heart Rate, Blood Pressure,
Oxygen Saturation
Pupil Diameter, Respiration
Rate, End Tidal CO2

Drug Administration

Visual Analog Scales

Adjectives (Subjective and
Observer)

ARCI

Street Value

DSST, Flicker Fusion,
Maddox Wing

Recorded Continuously

196 Psychopharmacology (2010) 212:193–203

effects of 0, 5, 10, and 15 mg/10 ml of oxycodone,
hydrocodone, and morphine were tested. After completion
of the pilot study, the high dose of each drug was increased
to 20 mg/10 ml. Of the remaining 16 individuals screened,
five were lost to follow-up and one failed to meet inclusion/
exclusion criteria due to opioid physical dependence. Ten
participants enrolled into the study; one was withdrawn due
to noncompliance and nine completed. Eight of the
completers were male and one was female; all were
Caucasian (32±2.3 years of age) and all were daily
cigarette smokers. Current other drug use in the 30 days
prior to screening reported on the Addiction Severity Index
and other screening instruments was common, but no
participants were physically dependent on any drug. Six
participants reported marijuana use (11.0±3.7 days out of
the past 30), four reported cocaine use (5.3±2.8 days out of
the past 30), five reported use of benzodiazepines (4.1±
1.3 days out of the past 30) and amphetamine (2.0±1.0 days
out of the past 30) and seven reported alcohol use (7.2±
2.4 days out of the past 30). All participants reported
recreational use of prescription opioids, most commonly
methadone and oxycodone, with an average reported
current use of 10 days per month (±2.3). Three participants
had used heroin in the month preceding screening. All
participants not only reported using opioids intravenously
(an a priori inclusion criterion) but also reported oral and

intranasal recreational opioid use. Two participants reported
past histories of treatment for opioid use, but none were
seeking treatment at the time of study entry.

Time course

Physiological measures As shown in Fig. 1, all three
opioids produced dose-dependent decreases in pupil
diameter and oxygen saturation. The highest dose of all
drugs produced significant decreases in pupil diameter
relative to placebo. This effect generally appeared within
5 min of drug administration and was evident for a
majority of the 6 h session following oxycodone and
morphine dosing. The effects of hydrocodone only lasted
for 2 h after dosing. The decreases in oxygen saturation
relative to placebo were evident within 5 min of drug
administration and persisted approximately 20 min, with
post hoc tests revealing statistical significance after only
20 mg oxycodone administration.

All three opioids produced dose- and time-dependent
increases in expired CO2 (i.e., interaction of drug condition
and time; F189,1512=1.2, p=0.04) and decreases in respiration
rate (i.e., main effects of drug condition and time; F9,72=2.9,
p=0.006, F21,168=3.9, p<0.001; data not shown). No significant dose-related main effects or interactions were observed on the cardiovascular measures. 0 30 60 90 120 150 180 210 240 270 300 330 360 2.4 2.7 3.0 3.3 3.6 3.9 4.2 4.5 4.8 Morphine D ia m e te r (m m ) Oxycodone Hydrocodone 5 10 20 0 BL 0 30 60 90 120 150 180 210 240 270 300 330 360BL 0 30 60 90 120 150 180 210 240 270 300 330 360BL 0 30 60 90 120 150 180 210 240 270 300 330 360BL 0 30 60 90 120 150 180 210 240 270 300 330 360BL 0 30 60 90 120 150 180 210 240 270 300 330 360BL 94 95 96 97 98 99 100 Time (min) Time (min) Time (min) Pupil Diameter Dose (mg, i.v.) A rt e ri a l O 2 S a tu ra tio n ( % ) Oxygen Saturation 5 10 20 0 Dose (mg, i.v.) 5 10 20 0 Dose (mg, i.v.) Fig. 1 Data are shown for mean values (n=9) for pupil diameter (top panel) and oxygen saturation (bottom panel) after administration of morphine (left column), oxycodone (middle column), and hydrocodone (right column) as a function of time (X-axis) since drug administration in the 6-h session. Error bars omitted for clarity. Filled symbols indicate a significant difference from the corresponding placebo time point. Time course analysis revealed significant interactions of dose and time condition for pupil diameter and oxygen saturation (F189,1509=2.0, p< 0.0001; F189, 1507=1.4, p=0.001, respectively) Psychopharmacology (2010) 212:193–203 197 Subject- and observer-rated measures Dose- and time- dependent increases were observed on responses to “Do you feel any DRUG EFFECT?” and “How much do you LIKE the drug?” following the administration of all three opioids, with the exception that the intermediate and low morphine doses produced effects of similar magnitude (Fig. 2). The high dose of oxycodone and morphine, but not hydrocodone, increased responses to these items, with statistically significant effects evident approximately 10 min after dosing and dissipating less than 30 min after dosing. For each drug, the effects of lower doses dissipated more quickly than those of higher doses. Similar effects were observed on ratings of “How HIGH are you?” and “Does the drug have any GOOD EFFECTS?” (i.e., interaction of drug condition and time; F333,2662>1.3, p<0.0001; data not shown). The low dose of morphine produced transient increases on ratings of “Does the drug have any BAD EFFECTS?” (i.e., main effect of drug condition; F9,72=2.1, p=0.04; data not shown). The high dose of oxycodone produced transient increases for ratings of “Does the drug make it DIFFICULT TO CONCENTRATE?” (i.e., main effects of drug condition and time; F9,72=2.4, p=0.02, 17,136=3.9, p<0.0001; data not shown). All three opioids also produced dose- and time- dependent increases (i.e., significant interaction effect) on the MBG scale of the ARCI (F108,864=1.5, p<0.001), Subject-Rated Opioid Agonist Adjectives (F144,1151=1.5, p<0.0001), Observer-Rated Opioid Agonist Adjectives (F144,1142=1.9, p<0.0001), and Street Value (F135,1080= 1.7, p<0.0001; data not shown). Ocular and performance tasks No significant dose-related main effects or interactions were observed on the performance measures. Peak effects Figure 3 shows outcomes for four representative measures: expired CO2, Observer-Rated Opioid Agonist Adjectives, “Does the drug have any GOOD EFFECTS?,” and Street Value. Table 2 shows mean nadir/maximum (depending on the direction of the effect) values from other measures not shown in Fig. 3 for which a significant effect of drug condition was observed. Physiological measures The 10 and 20 mg doses of all three drugs produced significant increases in expired CO2 (Fig. 3). A similar pattern was observed for pupil diameter and 0 5 10 15 50 95 140 185 230 275 320 365 0 10 20 30 40 50 60 0 10 20 30 40 50 60 BL 0 5 10 15 50 95 140 185 230 275 320 365BL 0 5 10 15 50 95 140 185 230 275 320 365BL 0 5 10 15 50 95 140 185 230 275 320 365BL 0 5 10 15 50 95 140 185 230 275 320 365BL 0 5 10 15 50 95 140 185 230 275 320 365BL Morphine Oxycodone Hydrocodone Time (min) Time (min) Time (min) “Do You Feel ANY DRUG Effect?” V is u a l A n a lo g S co re ( m m ) V is u a l A n a lo g S co re ( m m ) 5 10 20 0 Dose (mg, i.v.) “How Much Do You LIKE the Drug?” 5 10 20 0 Dose (mg, i.v.) 5 10 20 0 Dose (mg, i.v.) Fig. 2 Data are shown for mean values (n=9) for responses to “Do you feel any DRUG EFFECT?” (top panel) and “How much do you LIKE the drug?” (bottom panel) after administration of morphine (left column), oxycodone (middle column), and hydrocodone (right column) as a function of time (X-axis) since drug administration in the 6-h session. The maximum score is 100. Error bars omitted for clarity. Filled symbols indicate a significant difference from the corresponding placebo time point. Time course analysis revealed significant interactions of dose and time condition for “Do you feel any DRUG EFFECT?” and “How much do you LIKE the drug?” (F333,2661=1.4, p<0.0001; F333,2662=1.3, p=0.002, respectively) 198 Psychopharmacology (2010) 212:193–203 oxygen saturation (see Table 2). No significant effects were observed for respiration rate or the cardiovascular measures. Subject- and observer-rated measures All three drugs produced significant, dose-dependent increases on the Observer-Rated Opioid Agonist Adjective Scale, the visual analog scale item “Does the drug have any GOOD EFFECTS?” and Street Value estimates (Fig. 3). Post hoc tests revealed that the 20 mg dose of each drug produced significant increases on these measures. The intermediate and low doses of the drugs also produced significant increases on some measures. Table 2 shows the peak/nadir values of the other measures for which a significant effect of drug condition was observed: “Do you feel any DRUG EFFECT?,” “How HIGH are you?,” “How much do you LIKE the drug?,” “Does the drug have any BAD EFFECTS?,” and “Does the drug make it DIFFICULT TO CONCENTRATE?” from the visual analog scale, the MBG, PCAG, and AMPH scales of the ARCI and the Subject-Rated Opioid Agonist Adjectives (F9,72>2.4, p≤0.02).

Two exceptions to the pattern of results observed with
subject- and observer-rated measures (see Table 2 and

Fig. 3) occurred on responses to “Does the drug have any
BAD EFFECTS?” and “Does the drug make it DIFFICULT
TO CONCENTRATE?”. Only the low dose of morphine
significantly increased ratings of “Does the drug have any
BAD EFFECTS?” while only the high dose of oxycodone
significantly increased ratings of “Does the drug make it
DIFFICULT TO CONCENTRATE?”.

Ocular and performance tasks The high dose of morphine
and oxycodone significantly decreased the score on the
CFF 2 (F9,72=2.7, p=0.01). The high dose of oxycodone
and hydrocodone both increased scores on the Maddox
Wing task (F9,72=4.2, p<0.001). No significant effects were observed on the outcome measures for the DSST. Relative potencies Of the 18 measures for which a significant peak effect was observed, nine valid potency estimates were calculated for oxycodone and six valid potency estimates were calculated for hydrocodone. Table 3 shows these estimates with 95% confidence intervals. The table also includes those measures 36 38 40 42 44 46 48 50 m m H g 0 5 10 20 5 10 20 5 10 20 5 0 10 15 20 25 30 35 40 45 50 6 8 10 12 14 16 18 20 22 24 48 0 5 10 20 5 10 20 5 10 20 0 5 10 20 5 10 20 5 10 20 0 5 10 20 5 10 20 5 10 20 0 10 20 30 40 50 60 70 100 Morphine Oxycodone (mg,i.v.) Hydrocodone Morphine Oxycodone (mg,i.v.) Hydrocodone Expired End-Tidal CO2 R a tin g S ca le V is u a l A n a lo g S co re ( m m ) Does the Drug Have Any GOOD Effects? Opioid Agonist Scale - Observer U .S . D o lla rs Street Value Fig. 3 Data are shown for mean values (n=9) for expired CO2 (top left panel), Observer-Rated Opioid Agonist Adjectives (top right panel), “Does the drug have any GOOD EFFECTS?” (bottom left panel), and Street Value (bottom right panel) as a function of dose (X- axis). Brackets indicate ±1 SEM. A significant effect of Dose Condition was observed for all four measures (F9,72≥7.8, p< 0.0001). Filled symbols are significantly different from placebo (Tukey test; p<0.05) Psychopharmacology (2010) 212:193–203 199 for which the assay was invalid along with the specific assumptions violated. For the valid oxycodone potency assays, oxycodone was more potent than morphine on seven measures. For the valid hydrocodone potency assays, hydrocodone was less potent than morphine on five measures. Importantly, the potency differences for both drugs were modest (i.e., average potency ratios of 1.03 and 0.92 for morphine relative to oxycodone and hydrocodone, respectively). When comparing across the four measures (ARCI MBG and AMPH, Subject-Rated Opioid Agonist Adjectives and Street Value) that had valid potency estimates for both oxy- codone and hydrocodone, the potency relationship was generally oxycodone > morphine > hydrocodone.

Discussion

Intravenous administration of oxycodone, hydrocodone,
and morphine to nonphysically dependent opioid users
produced prototypical mu opioid agonist-like effects (e.g.,
miosis, increased ratings of drug liking and good effects)
and was well tolerated (i.e., no serious adverse events
occurred). Abuse potential is a composite of both positive
and negative subjective effects, and there was little
evidence in the present study of negative subjective effects

for these three opioids. The time course and peak effects
were qualitatively and quantitatively similar across drugs,
indicating a comparable potential for abuse of intravenous
oxycodone and hydrocodone relative to the positive
control, morphine. While potency differences were noted
between oxycodone and hydrocodone in comparison to
morphine, these differences were very modest (i.e., less
than two-fold).

The rapid onset of pharmacodynamic effects (i.e., within
5 min of dosing) following active drug administration is
consistent with previously published pharmacokinetic data
for oxycodone and morphine (Leow et al. 1992; Stanski et
al. 1978). This finding is also in agreement with results of
previous human laboratory studies that examined the time
course of the pharmacodynamic effects of oxycodone and
morphine (Marsch et al. 2001; Tarkilla et al. 1997).

The physiological and subjective effects of hydrocodone
dissipated more rapidly than those of oxycodone and
morphine. However, comparison of the hydrocodone curves
to doses of morphine and oxycodone yielding comparable
effects show that the effects of intermediate doses of those
drugs also produced effects of shorter duration compared to
the highest test doses of oxycodone and morphine.
Moreover, although not reported in the “Results,” time to
peak values for corresponding doses of the three drugs did

Table 2 Peak values for measures with a significant effect of drug condition. Bolded values are significantly different from placebo

Outcome measure Placebo Morphine (mg) Oxycodone (mg) Hydrocodone (mg)

5 10 20 5 10 20 5 10 20

Physiological

Pupil diameter* 3.9 3.4 3.0 2.6 2.8 2.6 2.4 3.2 3.0 2.8

Oxygen saturation* 97.1 96.9 96.4 95.6 96.2 95.5 94.0 96.7 96.0 95.4

Subject-rated

Visual analogs

High 4.7 27.4 30.1 49.8 26.6 37.7 55.8 12.8 27.2 40.1

Drug effect 5.0 30.1 32.9 51.4 26.2 39.0 55.4 14.7 31.3 43.2

Like 5.3 38.7 37.2 53.6 28.0 44.2 59.3 17.3 34.7 41.7

Bad effect 1.3 22.2 10.8 10.3 2.0 0.6 4.8 0.6 2.9 12.3

Difficulty concentrating 0.6 1.2 0.0 9.1 0.7 8.4 15.8 0.0 5.4 2.8

ARCI

PCAG 4.6 4.4 4.7 4.8 5.7 5.3 6.4 3.9 5.8 4.8

AMPH 2.6 2.9 3.3 4.7 2.9 3.6 3.9 2.7 2.9 3.6

MBG 1.7 4.8 5.2 9.1 4.8 6.2 8.4 3.9 5.8 6.9

Agonist scale 9.8 14.6 14.1 18.1 14.3 17.6 19.9 13.4 14.7 16.9

Ocular tasks

Maddox wing 4.1 4.3 5.0 6.3 5.2 6.3 7.3 4.8 5.8 6.6

Flicker/fusion* (#1) 33.8 32.0 32.1 30.2 31.9 33.2 30.5 31.7 33.6 31.6

Flicker/fusion* (#2) 33.7 31.3 31.0 29.5 32.1 32.8 30.2 31.5 33.4 31.9

Measures were analyzed as peak maximum score unless nadir is indicated (*). Values are mean scores (n = 9) for placebo, morphine, oxycodone
and hydrocodone

200 Psychopharmacology (2010) 212:193–203

not differ from one another. Overall, the time course data
reveal that the three drugs are very similar in time-action
profile (with differences dependent upon dose), and this is
consistent with their similar reported elimination half-lives
(i.e., 2–4 h; reviewed in Trescot et al. 2008).

The physiological effects of all three drugs generally
lasted throughout the 6-h session, while the subjective
effects dissipated much earlier; this is also concordant with
findings of previous studies that have tested the effects of
intravenous opioids (Abreu et al. 2001; Marsch et al. 2001).
The differences in time course between physiological and
subjective effects are important given that individuals may
choose to re-inject an opioid once the subjective effects
have subsided and be unaware that potentially dangerous
physiological effects (e.g., respiratory depression, decreased
oxygen saturation, or increased expired CO2) remain that
could be potentiated by additional dosing.

The highest dose of all three opioid drugs produced
significant effects on peak/nadir physiological and
subjective outcomes characteristic of mu opioid agonists
(e.g., miosis, increased expired CO2, and ratings of

liking), which is also consistent with previous research
examining parenteral opioid administration (Comer et al.
2008, 2009; Lamb et al. 1991; Tarkilla et al. 1997).
Moreover, effects observed here on ocular tasks (i.e.,
decreases in CFF threshold and increases in exophoria) are
concordant with previous studies (Saarialho-Kere et al.
1989; Walsh et al. 2008; Zacny and Gutierrez 2003). As in
some earlier studies (Comer et al. 2008; Walsh et al.
2008), there were no effects on DSST performance
suggesting that doses of these opioids producing robust
subjective effects do not reliably impair performance or
that this task may be insensitive to the effects of opioid
administration.

The peak effects of oxycodone were of greater
magnitude, but not significantly different, compared to
those of morphine and hydrocodone, which was sup-
ported by the relative potency analysis (i.e., valid
potency ratios indicated a relationship of oxycodone >
morphine > hydrocodone). A number of potency ratios
could not be calculated due to violations of the
preparation assumption (Table 3). These violations were

Table 3 Relative potency estimates and 95% confidence intervals based upon Finney’s (1964) bioassay using logarithmic doses

Outcome measure Morphine relative
to oxycodone

Confidence
intervals

Assumptions
violated

Morphine relative
to hydrocodone

Confidence
intervals

Assumptions
violated

Physiological

Pupil diameter* – – 2, 3 – – 2

Oxygen saturation* – – 3 – – 3

Expired CO2 – – 2, 3 0.975 0.793–1.188

Subject-rated

Visual analogs

High 1.111 0.874–1.493 – – 3

Drug effect 1.054 0.828–1.377 – – 3

Like 1.020 0.634–1.699 – – 3

Good effect 1.051 0.785–1.458 – – 3

Bad effect – – 3, 4 – – 2, 4

Difficulty concentrating – – 3 – – 4

ARCI

PCAG – – 3, 4 – – 4

AMPH 0.919 0.455–1.494 0.752 0.055–1.222

MBG 1.018 0.661–1.613 0.862 0.352–1.367

Agonist scale 1.263 0.936–2.175 0.895 0.402–1.455

Street value 1.168 0.971–1.472 0.928 0.666–1.228

Ocular tasks

Maddox wing – – 3 – – 3

Flicker/fusion* (#1) – – 4 – – 1, 3, 4

Flicker/fusion* (#2) 0.667 0.017–1.053 – – 3, 4

Observer-rated adjectives – – 2, 3 1.116 0.880–1.496

All outcome measures, for which significant effects of dose condition were observed in the peak maximum/nadir analyses (denoted by *) were assayed.
If an assay was invalid, the assumptions violated are noted by number below (1=Linearity, 2=Parallelism, 3=Preparation, 4=Regression). Morphine is
the reference drug. Relative potency is expressed as mg morphine necessary to produce the same effect as 1mg of oxycodone or hydrocodone

Psychopharmacology (2010) 212:193–203 201

likely due to the effects of the highest dose of oxycodone
and the lowest dose of hydrocodone producing effects
outside the upper and lower range, respectively, of those
produced by morphine, further supporting the potency
relationship obtained with the valid analyses. These data
bolster the argument that these widely prescribed opioid
analgesics have comparable potential for abuse across
routes of administration and extend previous findings to
sporadic opioid users.

Our finding that oxycodone was more potent than
morphine and hydrocodone is consistent with the results
of some previous preclinical and clinical studies (Meert and
Vermeirsch 2005; Zacny and Gutierrez 2003, 2008, 2009;
Zacny and Lichtor 2008). However, other work has
suggested that orally administered oxycodone and hydro-
codone are equipotent to one another (Walsh et al. 2008),
and that parenteral doses of hydrocodone and oxycodone
are equipotent to morphine (Comer et al. 2008; Fraser and
Isbell 1950; Jasinski and Martin 1967). The reasons for
these different potency ratios observed across studies is
unknown but could be due to a number of factors including
the study population, route of administration, and the
method used to assess potency.

In closing, these data suggesting comparable abuse
potential for intravenous hydrocodone, oxycodone, and
morphine have implications from both the regulatory and
clinical practice perspective. As noted above, oxycodone
is available in the USA in both combination and opioid-
only formulations and is regulated under Schedule II.
Hydrocodone alone is regulated under Schedule II but is
presently available in the USA only in combination
products, which fall under the less tightly regulated
Schedule III designation. Previously published studies
suggest that the presence of acetaminophen in opioid
combination products does not alter abuse potential
(Zacny et al. 2005; Zacny and Gutierrez 2008), so it may
be inferred that parenteral administration of hydrocodone
combination products would not result in significantly
different effects from those reported here for hydrocodone
alone. Thus, it is important that clinician prescribers
recognize that the Schedule III designation of these
hydrocodone products does not necessarily indicate lower
abuse potential and should prescribe with the same degree
of caution as with Schedule II opioids.

Acknowledgements This research was supported by a grant from
the National Institute on Drug Abuse (5R01DA016718-05) to Sharon
L. Walsh and by the University of Kentucky CRDOC. The authors
declare no conflicts of interest relevant to this project. The authors
with to thank Lori Craig, Jessica DiCentes and Elizabeth Tammen for
technical assistance and Stacy Miller, Todd McCoun, Pieter Steyn and
Marie Thompson for medical assistance.

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