Addicted Rats Main

JPM-06270; No of Pages 12
Journal of Pharmacological and Toxicological Methods xxx (2015) xxxxxx
Contents lists available at ScienceDirect
Journal of Pharmacological and Toxicological Methods

journal homepage: www.elsevier.com/locate/jpharmtox
Original article
Abuse liability assessment of hydrocodone under current draft

regulatory guidelines
David V. Gauvin , Margaret McComb, Robert Code, Jill A. Dalton, Theodore J. Baird
Department of Safety Pharmacology and Neurobehavioral Sciences, MPI Research Inc., Mattawan, MI, United States
a r t i c l e
i n f o
Article history:
Received 11 February 2015
Received in revised form 10 April 2015
Accepted 4 May 2015
Available online xxxx
Keywords:
Hydrocodone
Self administration
Drug discrimination
Drug dependence
Discontinuation syndrome
Withdrawal
Morphine
Oxycodone
Abuse liability
Methods
a b s t r a c t
Introduction: The abuse liability of hydrocodone was assessed in male SpragueDawley rats under the European
Medicines Agency, the International Commission on Harmonisation, and the U.S. Food & Drug Administration
draft guidelines for the non-clinical investigation of the dependence potential of medicinal products.
Methods: Self-administration, drug discrimination, and repeat-dose two week dependence liability studies were
conducted to compare hydrocodone to the prototypical opiates, morphine and oxycodone.
Results: Hydrocodone was self-administered, produced an opiate-like subjective discriminative generalization
prole and produced a signicant discontinuation syndrome following abrupt treatment cessation that was
quantitatively and qualitatively similar to morphine and/or oxycodone.
Conclusion: Hydrocodone has abuse liability more similar to Schedule II opiates than other Schedule III
compounds currently controlled under the U.S. Controlled Substance Act.
2015 Elsevier Inc. All rights reserved.
1. Introduction
Guidelines for regulatory review of all new psychoactive substances
for both human and veterinary approval have been disseminated by the
European Monitoring Centre for Drug and Drug Addiction (EMCDDA,
2009), the Committee for Medicinal Products for Human Use (CHMP)
of the European Medicines Agency (EMEA, 2006), the International
Conference on Harmonisation (ICH, M3[R2], 2009), and the United
States Food and Drug Administration (FDA, 2010). These guidelines
are intended to 1) help dene the scope of the term psychoactive substances and, 2) to put in place a sound methodological and procedural
basis for carrying out risk assessments in regard to health and social
risks of the use of, manufacture of, and trafc in these new psychoactive
substances that involve member states of both the 1961 United Nations
Single Convention on Narcotic Drugs and the 1971 United Nations
Convention on Psychotropic Substances.
A three-part, evidence-based preclinical risk assessment plan
requires standardized behavioral assays of self-administration, drug
discrimination, and dependence potential to be conducted in either rodents (contemporarily considered the primary model) or non-human
Corresponding author at: Dept NBS, MPI Research Inc., 54943 North Main Street,
Mattawan, MI 49071, United States. Tel.: +1 269 668 3336x1613; fax: +1 269 668 4151.
E-mail address: david.gauvin@mpiresearch.com (D.V. Gauvin).
primates. The results of these assays must be supplied prior to health

agency approval of any new chemical entity that 1) crosses the blood
brain barrier; 2) is pharmacologically similar to any known drug of
abuse; 3) has a novel mechanism of action; 4) produces psychoactive effects such as sedation, euphoria, or mood changes; or 5) has any direct
or indirect actions on other neurotransmitter systems associated with
abuse potential, such as dopamine, norepinephrine, GABA, acetylcholine, opioid, NMDA, and cannabinoid.
The chemical 4,5-epoxy-3-methoxy-17-methyl-morphinan-6-one
was given the drug name, dihydrocodeinone, when it was rst
marketed in Germany in the early 1920's it sold under the proprietary
name of Dicodid. It was never screened for abuse liability prior to
approval as a medicinal product. As translated and cited by Eddy,
Halbach, and Braenden (1957), hydrocodone addiction was reported
as early as 1927:
Mller de la Fuenta said that cases of addiction to dicodid were known
in 1927; 17 of the 280 questionnaires analysed by Wolff, in 1928,
reported dicodid addiction; and in 1930 Richtzenhain warned that
dicodidismus was then so often observed that one should be as
cautious with dicodid injection as one would be with morphine.
In the United States the nonproprietary or generic name adopted for
the drug was simply, hydrocodone. Hydrocodone combination products
http://dx.doi.org/10.1016/j.vascn.2015.05.003
1056-8719/ 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Gauvin, D.V., et al., Abuse liability assessment of hydrocodone under current draft regulatory guidelines, Journal of Pharmacological and Toxicological Methods (2015), http://dx.doi.org/10.1016/j.vascn.2015.05.003
D.V. Gauvin et al. / Journal of Pharmacological and Toxicological Methods xxx (2015) xxxxxx
(i.e., Vicodin, Hycotuss), the only legitimate U.S. drug products on

the market at the time, were placed into Schedule III of the Controlled
Substances Act (21 USCA, Chapter 13 801-971) in spite of differential
control of its analgesic equivalents oxycodone (Roxicodone,
Percocet) and morphine (Kadian, MS-Contin) into Schedule II.
The differential scheduling action was approved under the premise
that the likelihood of acetaminophen toxicity would limit or minimize
the abuse of hydrocodone pharmaceutical products (cf Commission on
Narcotic Drugs: The Single Convention on Narcotic Drugs; Schedules:
E/CN.7/AC.3/9/Add.1; 18 November 1958; Eddy, Halbach, & Braenden,
1956). In the conclusions of these early reviews, hydrocodone was considered to be pharmacologically equivalent to morphine with respect to
analgesia, CNS depression, and dependence potential. Reports in the
published literature and by the U.S. National Institute on Drug Abuse
indicate that hydrocodone-combination products are consumed in
large quantities without concomitant and signicant changes in liver
function proles that might have been predicted based on, for example,
acetaminophen content. The therapeutic effects of hydrocodone, its
abuse potential, and actual abuse history in the US were thoroughly
reviewed during the requisite 8-factor analyses for schedule control
actions. Full literature reviews have been conducted by both U.S. DEA
(2014) and U.S. Department of Health and Human Services (2014).
More recently, hydrocodone single entity and combination products
have been administratively placed into Schedule II (Drug Enforcement
Administration, 2014).
The present studies were designed to systematically assess and
compare the relative abuse liability of hydrocodone and the prototypical
CII opiates, morphine and oxycodone, using an integrative approach
consistent with the current standardized international regulatory
guidelines.
2. Material and methods

2.1. Subjects
Male SpragueDawley rats ordered from Charles River Laboratories
(Portage, MI), 78 weeks of age and weighing approximately
230260 g were used in these experiments. The preponderance of the
published reports of drug abuse models in animal species has indicated
a selective use of male animals. It is generally assumed that the chronic
nature of dosing regimens used in these studies render equi-effective
responses in animal subjects; no gender-differences were expected in
the direction, duration, or magnitude of behavioral and physiological
effects induced by the procedures set forth in the study plans, and
accordingly only males were used.
Animals in the self-administration and drug discrimination studies
were singly housed in solid bottom poly-boxes with non-aromatic
bedding. Animals in the drug dependence study were singly housed in
standard stainless-steel wire-bottom cages. Solid-bottom cages bedding
materials were not used in this latter study because 1) of the potential to
induce pica (Batra & Schrott, 2011) and the incidence of copraphagia
(Barnes & Fiala, 1958a,b, 1959; Barnes, Fiala, McGehee, & Brown,
1957; Iwomoto & Klaassen, 1977; Lugo & Kern, 2002; March & Elliott,
1954; Mullis, Perry, Finn, Stafford, & Sade, 1979) in rats. Access
to fecal boli containing behaviorally active concentrations of opiate
and opiate-related metabolites, therefore, represents a signicant
experimental confound in such a study plan, and was avoided by the
use of alternate wire bottom caging.
Fluorescent lighting was provided via an automatic timer for
approximately 12:12 hour light:dark cycle per day. Temperature and
humidity were monitored and recorded daily and maintained according
to standard operating procedures between 64 to 79 F and 30 to 70%,
respectively. The basal diet was block Lab Diet Certied Rodent Diet
#5002 (PMI Nutrition International, Inc.). The diet and tap water were
available ad libitum unless designated otherwise (see below). The
protocols governing these studies had prior approval of MPI Research

Institutional Animal Care and Use Committee.
2.2. Equipment
The self-administration and drug discrimination studies were conducted in standard rat two-lever operant chambers (ENV-008CT; Med
Associates, Inc. NH, USA) with a modied top for self-administration
(MED-008CT-B2) equipped with a syringe pump (PHM-100) located
in a specially constructed and locked box located on top of the soundattenuating cubicle (ENV-018MD). Each chamber was equipped with
two stimulus lamps (ENV-221M), two retractable levers (ENV112CM), house lamp (28 V DC, 100 mA, ENV 215M), a modular pellet
dispenser (ENV 203N-45), and exhaust fan. The operant chamber was
interfaced (SmartCtrl 8 Input, 16 Output Package) with an IBM-based
personal computer system capable of controlling 16 chambers. An
operant control and data collection software program for both drug discrimination and self-administration procedures (R. Code, MPI Research,
Inc.) was written and validated using MED-PC language. A total of
thirty-two identically-equipped chambers were used in these studies
that were located in two security-controlled, video monitored,
key-card accessed rooms of the test facility.
2.3. Surgery
Sterile surgical implantation of jugular catheters to enable the
self-administration study was conducted by Charles River Laboratories
(Portage, MI) using specially designed and manufactured catheters
(MPI Research, Inc.). Eighty-six percent of all implanted catheters
remained patent for up to 6 months under current laboratory standards
and procedures (Gauvin, Dalton, Baird, & Faqi, 2013). Catheters were
ushed regularly with normal sterile saline for injection (USP) and
locked with heparinized solutions (30100 IU/mL) of either 50%
dextrose or saline throughout the life of the catheter to prolong patency.
Saline ushing occurred immediately prior to and after selfadministration sessions. Patency was veried daily with presession
and postsession ushing of catheters. The resistance to ow was used
as the rst indicator of possible catheter occlusion. If catheter occlusion
was suspected, a systems check on the viability of the implanted catheters was conducted. Technicians would administer a 5 mg/kg dose of
methohexital (Brevital), or any equivalent short-onset, short-lived
barbiturate through the catheter. Animals were monitored for at least
5 min post injection for signs of lethargy, malaise, or unconsciousness.
If the catheter was patent, the animal would appear anesthetized
shortly following the infusion. Recovery from the system check would
take approximately 15 min.
2.4. Procedures
2.4.1. Self-administration
Details of the self-administration training and testing procedure are
similar to those previously described by Briscoe et al. (1999). The rat
self-administration procedure that has been adopted by the industry
and FDA is described as a single lever operant lever press response
under a xed-ratio 10 (FR10) schedule of cocaine deliveries with
session lengths of at least 1 h duration. Once animals demonstrated
day-to-day stability in responding for cocaine deliveries (less than
20% day-to-day variability in the total number of training drug deliveries for three consecutive days). Once each animal demonstrated stable
operant responding for cocaine infusion (0.56 mg/kg/injection)
for three contiguous days of training or maintenance sessions a series
of test sessions were planned (A-B-A study design). The rst series of
test sessions was conducted with the maintenance dose of cocaine
(0.56 mg/kg/injection) in this session the animal, for the rst time,
was allowed to respond for an unlimited number of injections over a
one-hour access period on each of three consecutive days. Following
the completion of the maintenance dose tests, an extinction test with

saline (vehicle) was scheduled. These operant conditioning procedures
make explicit use of the fact that drug-reinforced responding undergoes
extinction and eventually decreases in probability when a reinforcing
drug dose is replaced with vehicle (saline) or an ineffective drug reinforcer or drug dose. Complete doseresponse functions were conducted
for the training drug (cocaine) and morphine, hydrocodone, and
oxycodone for comparison. Using 32 rats each dose of a 5 dose test
article generalization function in a subset of 6 animals per dose can be
tested without repeat.
Each test was preceded by at least 3 contiguous days of cocaine
maintenance self-administration with 0.56 mg/kg/injection of cocaine
with less than 20% day-to-day variability. That is, all drug tests are
conducted following 3 cocaine baseline sessions (i.e. ABA design;
where A refers to the maintenance dose of cocaine, and B refers to
a novel test condition). Following the completion of each three-day
substitution test, the animals self-administered the maintenance
dose of 0.56 mg/kg/injection until stable behavioral output was
observed permitting the next scheduled substitution test.
2.4.2. Drug discrimination
Details of the training and test sessions are similar to Gauvin,
Harland, Michaelis, and Holloway (1989), Gauvin, Criado, Moore, and
Holloway (1990), and Harland et al. (1989).
As previously highlighted by Glennon and Young (2011), the administration of drugs can exert effects on behavior via sites of action that are
apart or aside from the CNS (p. 62). In preclinical abuse liability studies
it is imperative to think outside the box and be open to alternative
approaches to drug administration outside the restricted scope of the
IND enabling study design. Risk assessments must include actual
abuse patterns in the real world with the knowledge that drug abusers
will often not use the intended route of administration as used in
preclinical screening study designs. Rectal administration of tablets
(Coon, Miller, Kaylor, & Jones-Spangle, 2005; Stevenson & Hume,
1991), chewing of transdermal patches (Mrvos et al., 2012; Prosser,
Jones, & Nelson, 2010), or the insufation of crushed and pyrolyzed
opiate tablets (chasing the dragon) were not part of any preclinical
IND-enabling studies of opiates, but they are common routes-ofadministration in the opiate abusing population.
The NCE might affect behavioral activity via an action at neuromuscular junction, the peripheral or spinal opiate receptor, the autonomic
nervous system, or the site of (an accidentally inferior) injection. As
described by Jrbe (2011) the onset, offset, and potency of the discriminative properties of a drug may covary with the route-of-administration.
In risk assessment reviews of preclinical animal-related data it is imperative to include variations in the route-of-administration in order to
demonstrate or assess the relative risk of abuse in the real world when
the drug is used nonmedically (Rush, Vansickel, & Stoops, 2011). Thus,
an important part of the characterization of the mechanism of a druginduced change in behavior is the assessment of the relative contribution
of rates-of-change, metabolic processes, and distributional actions that
covary with routes of administration. One of these approaches is to
train and test via differing routes of administration (Glennon & Young,
2011; Schechter, 1973). For example, Craft and Howard (1998) have
previously shown equal potency between oral, subcutaneous, and intraperitoneal administration of nicotine with respect to the discriminative
stimulus properties of 0.5 mg/kg nicotine in rats. Therefore, differential
routes of administration were used for training and testing in this
study (oral, sc, and ip).
One group of 32 male rats were trained to discriminate between
20 mg/kg morphine or tap water administered orally (per os, po)
60 min prior to the training sessions in daily 30 minute two-lever operant sessions, under a xed-ratio 10 schedule of food reinforcement
(Group 1). Another group of 32 male rats was trained to discriminate
between 1.0 mg/kg oxycodone or saline administered subcutaneously
(sc) 30 min prior to the sessions (Group 2). Daily training sessions
continued until each rat emitted less than 20 responses prior to the
delivery of the rst food pellet and greater than 80% of total session responses were emitted on the stimulus appropriate lever. Training and
test sessions ended after 50 reinforcer deliveries or 30 min, whichever
occurred rst. Test sessions were identical to training sessions except
for the dose of drug administered before the session and during the
test session 10 consecutive responses on either lever produced a food reward. Tests were conducted with various doses of orally administered
morphine and hydrocodone (Group 1) or orally, intraperitoneal (ip),
and subcutaneous injections of oxycodone or hydrocodone (Group 2).
These time intervals were selected from published PK studies conducted with oxycodone and hydrocodone (Chan, Edwards, Wyse, & Smith,
2008; Cone, Darwin, Gorodetzkey, & Tan, 1978; Huang, Edwards, &
Smith, 2005; Lelas, Wegert, Otton, Sellers, & France, 1999; Tomkins
et al., 1997).
2.4.3. Dependence liability
Methods for assessing the dependence potential of morphine in rats
were developed by Akera and Brody (1968). While the procedure for
other species varies, the basic method adopted by the College on Problems of Drug Dependence (Brady & Lukas, 1984) is as follows: Ideally,
two evenly spaced injections per day are administered. The specic
patterns of dosing (qd, bid, tid, etc.) must be derived from established
pharmacokinetic data from the species used in these dependence liability studies. The Cmax, Tmax, and metabolic half-life of the compound will
determine the actual number of dose administrations and the interdose intervals that should be used to adequately ensure that plasma
concentrations are achieved and maintained throughout the full repeat
dosing cycle (Cone et al., 1978; Lelas et al., 1999; Tomkins et al., 1997).
Due to well characterized respiratory depression and self-mutilation
that is induced in rat subjects by even moderate doses of opiates, the initial dose administered in these types of repeat-dose study designs is
limited. Using an equivalent dosing strategy (see below), as tolerance
to the sedative, and respiratory depressive effects develops to the initial
dosing schedule, the maintenance dose was increased.
Rats were dosed over 14 days. The initial dose of both drugs was
20 mg/kg administered twice per day. The morning dose was, in effect,
a loading dose to achieve chronic equivalence from the start of treatment in order to provide a reference point to evaluate chronic tolerance
development. Based on the acute time course of action of this dose previously reported in the scientic literature, the dosing times of (7:00 am
and 5:00 pm) were selected allow an approximate 12 h average dose
interval. These dose intervals (10 and 14 h) were used to ensure relative
continuity of CNS drug exposure with adequate recovery between drug
administrations.
In order to ensure that the selected dosing schedule achieved both
equivalency of peak responses as well as continuity of drug effect
between doses, a behavioral scoring system of ataxia assessment, rst
developed to measure CNS depression (Boisse & Okamoto, 1978a,b;
Okamoto & Boisse, 1981; Okamoto, Boisse, Rosenberg, & Rosen, 1978;
Okamoto, Hinman, & Aaronson, 1981) was used, in part, to escalate
the dose of morphine and hydrocodone from day to day up from an
initial 20 mg/kg to a maximum approaching 300 mg/kg/day.
Group mean scores on the ataxia scoring system were determined
daily at 1:00 pm (6 h following the rst daily dose) during the chronic
dosing period. The lowest possible score of 0 implies no CNS impairment or depression. The highest score of 11 implies severely
depressed. On observation of scores of 6 or less, the daily dose of morphine and hydrocodone was increased to the next incremental level.
Scores of 7 or greater required additional review/consideration of the
clinical presentation by the study director to determine potential need
for increment.
Accordingly for hydrocodone and morphine treatment groups, over
the course of 15 days, the second of two daily doses of drug was increased from an initial dose of 20 mg/kg to the maximal tolerable dose
(dened as the overt expression of clinical signs of toxicity; scores of
11 or 12 on the ataxia scale). The morning daily loading dose may have
been different from the afternoon dose. When, or if, a maximum tolerable dose was reached the dose was maintained for the remainder of the
15 day treatment regimen. Based on previously published reports of
opiate dependence in rats, the maximum doses were expected to
approximate levels as high as 300 mg/kg/day (expressed as the base).
Doses were administered for 14 days and achieved a combined daily
dose of 300 mg/kg by Day 13 (often 150 mg/kg/rat twice daily). On Days
15 through 18 animals received sham injections of saline to control for
handling and injection conditioning.
Complete functional observational batteries (Moser, McCormick,
Creason, & MacPhail, 1988) were then conducted during the initial
withdrawal phase of the study (Days 16, 17, and 18 of the study
plan). Each rat was assessed as follows:
2.4.3.1. Functional observational battery. Each animal was observed for a
minimum of 3 min in a black plexiglass, open-eld observation box
measuring 20 in. by 20 in. by 8 in. Parameters evaluated were based
on those outlined in Moser et al. (1988) and Moser and Ross (1996).
2.4.3.2. Expected clinical signs. Based on the preponderance of scientic
reports appearing in peer-reviewed scientic journals chronic opiate
administration was expected to produce pica, gastroparesis, gastric
distention, constipation, aggression, irritability, and self-mutilation.
Treatments with a natural stimulant laxative (Senna) was initiated
prior to and during the chronic dosing regimen. This was intended to
mimic the standardized treatments of human patients receiving
long-term high dose opiates and to minimize the deleterious effects of
the opiates on gut motility during the course of drug administration
on this study.
Placement of aspen wood blocks, Nyla bones, and metal chain
rings into the cages were used as added environmental enrichments
for singly housed rats per MPI Research SOPs and also was intended to
help ameliorate the incidences of self-mutilation.
Peripheral histamine is released during opiate administrations in
both humans and animal subjects. Histamine-induced itching in the
limbs typically results in scratching, picking (crank bugs), and biting
in human opiate addicts and self-mutilation of paws and limbs in
morphinized animals. Cleansing with Novasan and the presence of
the additional environmental enrichments were intended to reduce
the potential need for medical intervention during this study. Part of a
clear demonstration and validation for dependence of the opiate
type were intended to be requisite clinical ndings.
During the withdrawal phase of the study it was expected that animals in both drug treatment groups would display marked or severe diarrhea and an expected body weight loss that could achieve 15 g/day
these are considered prototypical withdrawal signs from opiate dependence and an important target to be demonstrated in this study. This
bodyweight loss is usually self-limiting, short-lived, and was expected
to abate by the 3rd or 4th day of the withdrawal phase of the study. No
need for treatment or medical intervention was expected.
All of these expected clinical signs were presented to the full IAUC
committee review of the protocol (Classication D of pain and distress) which approved and initiated the treatment plan and scheduled
veterinary consultations throughout the conduct of the dependence
liability study.
2.4.3.3. Food consumption. Each animal's food was weighed every other
day in order to get a rudimentary impression of food intake. With
rodent block diet, it is understood that such consumption would not
be a perfectly accurate measure of actual nutritional intake for each
rat. However, on the assumption that rats would lose or waste similar
amounts of block diet each day, the food consumption measure was
used to help discern incidences of pica, motoric effects, and gut motility
properties potentially associated with the chronic dosing regimens.
2.4.3.4. Body weights. Body weights were measured and recorded within
3 days of arrival, prior to randomization to treatment conditions, and
every day during the chronic dosing regimen. Body weights measured
following arrival are not included in this report. Animals were weighed
daily during the chronic dosing and withdrawal phases of the stud, and
as part of the individually scheduled FOBs.
2.5. Drugs
Normal sterile saline for injection (USP) was used as the vehicle for
all study designs and for sham injections in the dependence liability
study. Hydrocodone bitartrate, oxycodone hydrochloride, and
morphine sulfate pentahydrate were purchased from Mallinkrodt, Inc.
(Covidian Pharma, Inc., St. Louis, MO). Doses were weighed and
expressed as the base. For the oral morphine drug discrimination task,
normal tap water was used as the control vehicle condition.
As stated above, chronic high dose opiate treatments are known to
induce constipation, weight gain and, and in some cases, gastroparesis
in both human and animal research subjects. For the health and safety
of the animals on this study there was no need to further demonstrate
the full spectrum and magnitude of this major pharmacological effects
of the opiates used as positive control articles (i.e., morphine and
hydrocodone) by administration of an expanded range of (including
higher) doses.
As a preemptive treatment, two days prior to the initiation of dosing
and daily (approximately 1:00 pm) during the 15 day chronic dosing
regimen, each rat in Groups 2 & 3 received doses of a natural plant
derived stimulant laxative, senna, to ensure gut motility was maintained
during dose regimen.
An initial dose of 210 mg/kg (5.97 mL/kg volume) was selected for
administration. This initial dose was escalated upward in 50 mg/kg
increments, up to a maximum dose of 600 mg/kg to maintain fecal
output over the 2 week dosing period. Mengs, Mitchell, McPherson,
Gregson, and Tigner (2004) have previously demonstrated the relative
safety of up to 1500 mg/kg/day of senna treatments in rats exposed to
daily doses for 13 weeks with no signs of toxicity or rebound phenomena during abrupt cessation of treatments.
3. Results
3.1. Self-administration
All 32 rats were conditioned to initiate and maintain lever press
responding to receive a single iv dose of 0.56 mg/kg/infusion of cocaine.
Less than 20% day-to-day variability was maintained by such cocaine
doses throughout the study plan.
Fig. 1 compares the results of three consecutive daily substitution
tests conducted with various doses of cocaine (upper left panel),
morphine (upper right panel), hydrocodone (lower left panel), and oxycodone (lower right panel) in rats conditioned to initiate and maintain
stable patterns of self-administration of 0.56 mg/kg/infusion of cocaine
in the regulatory standard self-administration behavioral assay. Under
the recommendations of the current FDA guidance document, substitution tests are conducted from a stable behavioral cocaine-selfadministration baseline. That is, all substitution tests are initiated
following the demonstration of a day-to-day stability of cocaine
self-administration. Substitution tests with saline, a non-reinforcer,
engendered a typical extinction burst on Day 1 of substitution with
a downward staircase pattern of responding during Day 2 and Day 3
with respect to the total number of injections administered (all four
panels). The upper left panel shows the result of tests conducted with
various doses of cocaine tested in ascending order Cocaine tests demonstrated a typical inverted U-shaped pattern of dose-effect function
across the 1.25 log unit dose response function. Moderate doses of
0.32 and 0.1 mg/kg/injection maintained a higher number of selfinjections when compared to the higher doses of 0.32, 0.56, and
Fig. 1. The group mean total number of infusions self-administered during one-hour daily sessions is plotted as a function of available cocaine dose expressed in mg/kg/injection in 32 rats
conditioned to self-administer 0.56 mg/kg/infusion of cocaine in daily sessions (upper left panel). For comparisons, the group mean total number of infusions during substitution tests
conducted with three opiate derivatives: morphine (upper right panel), hydrocodone (lower left panel) and oxycodone (lower right panel) in animals conditioned to self-administer
0.56 mg/kg/infusion of cocaine. Each unlimited access cross-generalization test was conducted following at least 3 consecutive days of cocaine self-administration baselines. Bars represent
the daily mean intake of 32 rats (saline and 0.56 mg/kg/infusion cocaine) or six randomly selected rats tested for three consecutive days in one-hour unlimited access sessions at each
selected drug and drug dose. The open circles represent the grand mean of all three days of substitution. The averaged total number of infusions self-administered during one-hour
daily sessions is plotted as a function of available drug dose expressed in mg/kg/infusion. All drugs engendered a typical inverted U-shaped doseresponse function. All three opiates
were self-administered in rats conditioned to self-administer cocaine.
Cocaine and oxycodone data adapted from Gauvin, Dalton and Baird (2013, p 455).
1.0 mg/kg/injection of cocaine. All ve tested doses of cocaine sustained

a similar pattern and number of injections over the three days of
substitution when compared to vehicle control tests.
The upper right panel of Fig. 2 shows the results of substitution tests
conducted with the classic mu opioid agonist, morphine, in those rats
trained to self-administer cocaine (Fig. 1, upper left panel). Note the
abbreviated ordinal axis. Morphine produced a blunted or attened
inverted U shaped dose response function compared to the training
drug, cocaine. While consistent day-to-day patterns of self-injections
were demonstrated for each dose of morphine tested in this study, the
patterns and numbers of injections engendered in these tests were
very low across the tested dose range and were attributed to the pharmacodynamic properties of morphine in this limited one hour access
period study design. Similar low patterns of responding for morphine
in similar 1 hour access test sessions (e.g., less than 10 infusions) have
been demonstrated by Mierzejewski, Koro, Goldberg, Kostowski, and
Stefaski (2003) in SpragueDawley rats and by Snchez-Cardoso
et al. (2007), Snchez-Cardoso et al. (2009) and Garcia-Lecumberri
et al. (2011) in Lewis and Fischer 344 rats. With the catheter tip of the
indwelling catheters placed at or very near the entrance of the right atrium, these low patterns of morphine intake may be related to the direct
dynamic cardiovascular effects of intravenously administered morphine
in the rat (Fennessy & Rattray, 1971; Randich, Robertson, & Willingham,
1993; Thurston, Starnes, & Randich, 1993).
The lower left panel of Fig. 1 shows the results of substitution test
sessions conducted with ascending doses of hydrocodone in rats conditioned to maintain stable day-to-day intakes of 0.56 mg/kg/infusion of
cocaine interspersed between the specic dose substitution tests. Similar to cocaine, the maintenance drug and morphine, the prototypic
mu-opioid, hydrocodone engendered an inverted U-shaped function

when the total number of infusions self-administered was plotted as a
function of the selected test doses. The total number of injections for
each dose test was greater than those engendered during morphine
substitution tests.
Finally, the lower right panel of Fig. 1 shows the results of substitution tests conducted with oxycodone. Similar to hydrocodone,
oxycodone engendered more robust responding for self-injections
compared to the parent mu opioid, morphine. An inverted U-shaped
function was engendered across the 1.5 common log unit dose range
tested in this study.
For comparison purposes, Fig. 2 shows the results of the data in
Fig. 1, but expressed as the grand mean of the total drug intake over
all three days of substitution for each dose and drug tested to assess
the relative reinforcing properties on this study. The total drug intake
induced by all four drugs demonstrated a linear monotonic function
when plotted as a function of the tested doses. The dashed line in the cocaine dose-effect function shows the typical training dose used in standard cocaine 2-choice drug discrimination studies, which is based on
the interoceptive properties of the drug (Gauvin et al., 1989, 1990;
Harland et al., 1989). Rats self-administering iv cocaine titrated their
drug intake to a cumulative dose that was clearly above an equivalent
dose of ip administered cocaine required to establish discriminative
stimulus control in rats. The dashed lines in the morphine, hydrocodone,
and oxycodone dose-effect functions represent the 95% condence
limits for the ED50 values for full generalization to a 0.04 mg/kg
fentanyl discriminative stimulus cue in rats (Meert & Vermeirsch,
2005). All three opiates were self-administered via the iv route
to dose levels that exceeded the equi-effective subjective dose
Fig. 2. The averaged 3-day total amount of drug self-administered during the three consecutive one-hour daily sessions shown in Fig. 4. Data are plotted as a function of available cocaine
(upper left panel), morphine (upper right panel), hydrocodone (lower left panel) and oxycodone (lower right panel) in rats conditioned to self-administer a maintenance dose of
0.56 mg/kg/infusion of cocaine. Each point on the graphs represents the three-day averaged intake of 32 rats (saline and 0.56 mg/kg/injection) or six randomly selected rats from the
pool of trained rats. As described in Fig. 4, each drug and dose was tested for three consecutive days in one hour unlimited access sessions at each selected dose shown. The closed circles
represent the mean of all three days of substitution. The dashed lines show 1) the standard training dose of cocaine (10 mg/kg) in drug discrimination assays (upper left panel) or the 95%
condence limits for the ED50 (threshold) fentanyl-like cross-generalizations between morphine (upper right panel), hydrocodone (lower left panel) or oxycodone (lower right panel)
generated in a separate study in which rats were trained to discriminate the presence versus absence of 0.04 mg/kg of fentanyl by Meert and Vermeirsch (2005). The data show that each
drug tested in the self-administration paradigm induced self-injected doses that were equivalent to those that produce a subjective state that would establish and maintain stimulus
control of behavior.
associated with the s.c. administration of fentanyl in a standard FR10

two-lever fentanyl vs saline discriminative stimulus assay in rats.
With respect to the reinforcing properties of two commonly abused
Schedule II opiates, morphine and oxycodone, these data have
demonstrated that hydrocodone has qualitatively and quantitatively
similar positive hedonic/rewarding effects in the standard regulatory
required behavioral self-administration assay.
3.2. Drug discrimination
The drug discrimination assay has been used to assess the relative
similarity of interoceptive stimuli associated with drug administrations.
Fig. 3 shows the subjective similarity of hydrocodone and morphine in
rats trained to discriminate between 20 mg/kg orally administered morphine and water administered 60 min preceding sessions. Hydrocodone
engendered complete generalization to the morphine training stimulus
(top panel) with similar behaviorally disruptive effects on rates-ofresponding during the test sessions (lower panel). Morphine and
hydrocodone were equivalent in both subjective and rate-disruptive
effects on operant performance under a xed ratio 10 schedule of food
delivery.
Fig. 4 shows the cross generalization proles for various doses of
oxycodone administered by three routes of administration (sc, ip and
po) in rats trained to discriminate the presence versus absence of
1.0 mg/kg oxycodone administered subcutaneously 30 min before the
operant test sessions. All three routes of administration produced subjectively similar but differential potency doseresponse generalization
functions with corresponding changes in the rates-of-responding for
food deliveries during the sessions. The route-of-administration
demonstrated an ordered sensitivity relationship to oxycodone's
subjective and rate-altering effects of sc b ip b po and is consistent
with the known absorption-distribution-metabolism prole of
oxycodone in rats.
Similarly, Fig. 5 shows the cross generalization prole for

hydrocodone administered by sc, ip, and po administrations in those
rats trained to discriminate the presence versus absence of 1.0 mg/kg
sc administered oxycodone shown in Fig. 4, above. Hydrocodone
engendered equivalent and complete cross generalization with the
1.0 mg/kg oxycodone training stimulus with a similar route-ofadministration potency relationship of sc b ip b oral with respect to
both the subjective interoceptive (top panel) and rate-altering effects
(bottom panel) under the xed ratio 10 schedule of food deliveries
used in this study.
With respect to the subjective and motoric effects of two commonly
abused Schedule II opiates, morphine and oxycodone, the data have
demonstrated that hydrocodone has qualitatively and quantitatively
similar subjective and rate-altering effects in the standard regulatory
required behavioral drug discrimination assay.
3.3. Dependence liability
3.3.1. Clinical observations
Clinical signs related to stimulation of the autonomic nervous
system were salivation, lacrimation, chromodacryorrhoea (secretion of
red uid around eyes), and piloerection. The clinical nding of material
around the eyes was a routine, non-signicant nding related to
grooming. The lacrimal secretions are due to the Harderian gland secretions. The glands are located behind the rat's eyes and the secretions are
the result of porphyrin secretion that usually goes unseen except during
periods of poor grooming (illness, stress, lethargy, sleep, etc.; cf., Sharp
& LaRegina, 1998). Calls of material around nose-red were documented during predose, dosing, and withdrawal phases of the study plan.
There were no distinctive or physiologically signicant clinical ndings reported over the two week dosing period in the two opiate treated
groups. The equivalent dosing strategy maintained the normal appearance and clinically observable health status of the rats on study.
Fig. 3. Doseeffect generalization functions for morphine (closed circles, solid lines) and
hydrocodone (open circles and dashed lines) that were orally administered 60 min prior
to test sessions. Thirty-two rats were trained in a two-choice lever-press response drug
discrimination assay. Each rat was trained to discriminate the presence versus absence
of 20 mg/kg orally administered morphine (MOR TD) under a xed-ratio 10 (FR10) schedule of food reward. Top panel: Percentage of total session responses emitted on the morphine-appropriate lever following morphine or hydrocodone dose administrations.
Bottom panel: Group mean rates-of-responding on either lever during the 30 minute
test sessions expressed as a function of dose. The points about the S on the abscissa represent data from saline test sessions and the closed circle under the MOR TD represent
the data from tests conducted with the 20 mg/kg morphine training dose (n = 32). All
other points on the graphs represent the mean of 6 rats. Hydrocodone engendered qualitative and quantitative changes strikingly similar to morphine in this assay based on the
subjective effects (top panel) and motor-impairing effects (bottom panel) produced by
drug administrations.
Some calls of swelling were documented in 1 out of 16 rats in each of

the hydrocodone and morphine treatments groups.
During withdrawal 6 out of 16 hydrocodone rats and 7 out of 16
morphine treated rats were considered hypersensitive to touch.
Vocalization scores increased each day of withdrawal in both the
hydrocodone treated (3/16 to 7/16 calls) and morphine treated (3/16
to 7/16 calls) rats on Day 16 to Day 18, respectively. Both of these clinical signs are considered to represent classic signs of opiate withdrawal
in the rat.
During the FOBs conducted during the withdrawal phase of the
study clinical signs were documented for the hydrocodone and
morphine groups which included the following: a) pinpoint pupils,
b) changes in gait hindfeet walking on tip toes, or hunched body
Fig. 4. Doseeffect generalization functions for oxycodone tests conducted following subcutaneous (closed circles), intraperitoneal (open circles) and oral (half-lled circles) doses
administered 30 min prior to test sessions. Thirty-two rats were trained in a two-choice
lever-press response drug discrimination assay. Each of 32 rats was trained to discriminate
the presence versus absence of 1.8 mg/kg subcutaneously administered oxycodone (TD)
under a xed-ratio 10 (FR10) schedule of food reward. Top panel: Percentage of total
session responses emitted on the oxycodone-appropriate lever following various doses
of oxycodone administered via three different routes. Bottom panel: Group mean ratesof-responding on either lever during the 30 minute test sessions expressed as a function
of dose. The points about the S on the abscissa represent data from saline test sessions
and the closed circle under the TD represent the data from tests conducted with the
1.8 mg/kg oxycodone training dose (n = 32). All other points on the graphs represent
the mean of 6 rats. Oxycodone engendered dose-related monotonic doseresponse
functions for both the subjective effects (top panel) and motor-impairing effects (bottom
panel) produced by each route of administration. The order of oxycodone thresholds was
sc b ip b oral for both subjective and rate-altering effects.
Adapted from Gauvin, Dalton and Baird (2013).
position, and c) rapid respirations. None of these calls were made in

saline treated cohorts.
3.3.2. Body weights
Fig. 6 shows the changes in body weights in the dependence liability
study. Body weights are shown for each day of the 15-day escalating
dosing period which was initiated at twice daily oral administrations
of either tap water (control group) or 20 mg/kg of morphine or
hydrocodone. The individual doses were incremented upward across
Fig. 6. Changes in body weights from dependence liability study. Group mean body
weights for three groups of rats treated for 15 days with oral gavaged tap water (closed
black squares) or escalating doses of up to 300 mg/kg/day of hydrocodone (red lled
circles) or morphine (green lled triangles), and for three days following abrupt cessation
of opiate exposure (Days 16, 17, and 18). Each point represents the group mean and
standard error of the mean of 16 rats treated with water, hydrocodone, or morphine.
in the morphine and hydrocodone treatment groups experiencing the

initial onset of a classic opiate withdrawal syndrome. The degree of
withdrawal based on the magnitude of decrements in bodyweights
was limited by the intentional and preemptive treatment of a stimulant
laxative (senna) over the course of opiate treatments for the sake of the
health and safety of the rats, meant to diminish the intensity of constipation and/or gastroparesis known to be induced by opiates. Vehicle
control cohorts showed a continued normal weight gain during the
Day 1618 study interval.
Fig. 5. Doseeffect cross-generalization functions for hydrocodone tests conducted following subcutaneous (closed circles), intraperitoneal (open circles) and oral (half-lled circles) doses administered 30 min prior to test sessions. Thirty-two rats were trained in a
two-choice lever-press response drug discrimination assay. Each of 32 rats was trained
to discriminate the presence versus absence of 1.8 mg/kg subcutaneously administered
oxycodone under a xed-ratio 10 (FR10) schedule of food reward. Top panel: Percentage
of total responses emitted on the oxycodone-appropriate lever following various doses of
hydrocodone administered via three different routes: subcutaneous, intraperitoneal, and
oral gavage. Bottom panel: Group mean rates-of-responding on either lever during the
30 minute test sessions expressed as a function of hydrocodone test dose. The points
about the S on the abscissa represent data from saline test sessions. All points on the
graphs represent the mean of 6 rats tested with various doses of hydrocodone administered following one of three different routes. Hydrocodone engendered dose-related
monotonic doseresponse cross generalization functions for both the subjective effects
(top panel) and motor-impairing effects (bottom panel) produced by each route of administration. The order of hydrocodone thresholds for oxycodone-like response choice and
response rates was sc b ip b oral. Doses greater than 32 mg/kg PO hydrocodone were
not tested for the sake of animal health and well-being.
successive days using an equi-effective dosing strategy to a nal dose on

Day 15 of twice daily administrations of 150 mg/kg of either morphine
or hydrocodone. Vehicle control animals received equal volumes as
their drug treated cohorts. The nal dose administration occurred on
the evening of Day 15. Body weights on Days 16, 17, and 18 reect the
rst three days of the discontinuation syndrome. There was a
bodyweight loss over the course of dosing in both drug treated groups
when compared to tap water control animals (Day 1 to Day 15). A
more dramatic weight loss was demonstrated on Days 16 through 18
3.3.3. Food consumption

Fig. 7 shows the relative changes in food consumption over the study
duration. Over the 15-day repeat dose incrementing phase of the study
both morphine and hydrocodone treated rats consumed much less food
than their vehicle control cohorts. While the control group showed stable intake over the study, both opiate treatments appeared to engender
a similar drop in food consumption across the 15 day repeat dose phase
of the study. The change in food consumption could have been attributed to the pica associated with opiate treatments in rats or a reduced
motivation to eat.
3.3.4. Functional observational batteries
FOBs can be organized into measures of functional domains. For organization and ease of reporting toxicology study designs are generally
using these functional domains. is most often reported using stratied
neurobehavioral functions.
3.3.4.1. Activity/arousal measurements. There were no functional differences between treatment groups on any measure of activity/arousal
during the predose FOB evaluation.
The ease of removal scores were lower in the hydrocodone and
morphine treatment groups on Day 7 of dosing when compared to
their vehicle control cohorts. On Day 15 the ease of removal scores
were low for both opiate treatment groups, but only the morphine
treated animals were statistically lower than vehicle controls. General
arousal scores for both hydrocodone and morphine treated groups
were statistically higher than their vehicle control cohorts on Day 15 following the highest dose of 150 mg/kg/dose administered on this study.
Fig. 7. Changes in food consumption from dependence liability study. Group mean of the
available food portions weighed daily over the 18 days of the dependence liability
study. Each point represents the averaged food in the cages for three groups of rats treated
for 15 days with tap water (black closed squares) or escalating doses of up to
300 mg/kg/day of hydrocodone (red lled circles) or morphine (green lled triangles),
and for three days following abrupt cessation of opiate exposure (Days 16, 17, and 18).
The lower food portions reported for hydrocodone and morphine treated rats reect
1) the induction of pica by opiate administrations, 2) smaller meal sizes, or 3) opiate
induced constipation (illness).
During the withdrawal phase hydrocodone and morphine treated

rats demonstrated statistically signicant increases in ease of removal
and handling reactivity scores on all three days of withdrawal (Days
16, 17, and 18). General arousal scores were also elevated on the
rst and second day of withdrawal (Days 16 and 17) in the opiate treated groups when compared to vehicle control cohorts, but returned to
normal by the third day of withdrawal (Day 18). The total number
of rearings counted during the 3-minute open eld arena test was
also signicantly higher in the hydrocodone and morphine treatment
groups on the rst two days of withdrawal (Days 16 and 17) when
compared to saline treated control cohorts. Increases in measures of
ease of removal, handling reactivity, general arousal, and rearings are
considered to be classic signs of opiate withdrawal in rodents.
3.3.4.2. Autonomic measurements. There were no functional differences
between treatment groups on any autonomic nervous system measurement during the predose FOB evaluations. There were no signicant
group differences in any measure of autonomic function on Day 7 of
repeat dosing. On the last day of dosing, the morphine treated animals
exhibited a statistically signicant increase in the total number of fecal
boli deposited within the open eld following 3 min of monitoring.
The difference of 1 fecal boli (between 4.8 and 3.8) in the opiate
treatment groups was not considered to be physiologically signicant
or indicative of differential pharmacological activity across these
treatment groups.
During the withdrawal phase, group differences in the total number
of fecal boli excreted and counted during the 3-minute open eld
assessments were not physiologically meaningful due to the use of the
senna treatments during the chronic dosing phase to control or regulate
fecal output in the hydrocodone and morphine treatment groups. Also
relevant to the lack of differentiation in the open eld assessment is
the relative timing and brevity of this manipulation in relation to the
temporal onset and full expression of the withdrawal syndrome. No
other signicant changes in autonomic measures were noted during
the withdrawal phase of this study.
3.3.4.3. Neuromuscular measurements. There was a single neuromuscular
function endpoint that demonstrated statistically signicant differences
between the treatment groups. Stereotypy calls were distributed

between scores of 1 and 2 in the vehicle controls (4/16 1 and
12/16 2) compared to hydrocodone group (12/16 1 and
4/16 2) and morphine groups (10/16 1 and 6/16 2) cohorts.
A score of 1 represents a call of alert and periodic snifng spell in the
air and a score of 2 represents a call of constant snifng on the wall
or oor. While statistically signicant, the distributional differences between groups were not considered to be physiologically relevant or a
reason to redistribute group cohorts prior to the initiation of dosing.
During the Repeat Dose Phase of the study, there was no statistically
signicant group differences on any measure of neuromuscular function
during FOBs conducted on Day 7 or 15. Following abrupt cessation of
opiate treatments on the evening of Day 15, the gait assessment of
rats in the hydrocodone treated group was reported to be abnormal
on Days 2 and 3 (Days 16 and 17) of withdrawal, with corresponding
gait alteration observed in the morphine group on Day 1 and Day 3 of
withdrawal when compared to untreated cohorts (Days 16 and 18).
Additionally, signicantly higher stereotypy scores were recorded on
the rst two days of withdrawal in the opiate treatment groups when
compared to their vehicle control cohorts. Grip strength and hindlimb
splay scores remained unaffected during opiate withdrawal on this study.
3.3.4.4. Physiological measurements. There were no functional differences
between treatment groups on any physiological measure during the
predose (Day 1) or repeat dose phase of this study (Days 7 and 15).
During the withdrawal phase of the study pinpoint pupils and rapid
respirations were reported in the two opiate treated groups.
Distributional score differences between the three treatment groups
on measures of respiration were recorded on Day 1 of withdrawal
(Study Day 16). Scores of 0 (normal respirations) and 1 (rapid or
slowed breathing, to be identied by comment) were given on Day
16. All rats in the vehicle control group (16/16) received scores of 0.
The hydrocodone group received scores of 0 (10/16) and 1 (6/16),
and the morphine treatment group received scores of 0 (13/16) and
1 (3/16). Other allowable scores representing labored, irregular or
difcult breathing (score of 2), rales (score of 3) or dyspnea, unusually
deep breathing (score of 4) were not documented in any group in this
study. These distributed scores of 0 and 1 on Day 16 resulted in a statistically signicant difference between the vehicle and hydrocodone
treatment groups (CochranMantelHaenszel test, p b 0.05).
Body weights also decreased during withdrawal as shown in Fig. 6.
3.3.4.5. Sensorimotor measurements. There were no functional
differences between treatment groups on any sensorimotor measure
during the predose FOB. Additionally, there were no statistically- or
physiologically-signicant differences between opiate treated and saline treated groups on Day 7 of dosing on any measure of sensorimotor
function. On Day 15 distribution differences in scores of 0, 1, and 2
were noted between groups: the hydrocodone treated group had scores
distributed between 1 (8/8) and 2 (8/8) compared to vehicle cohorts (1: 1/16, 2: 14/16; 3:1/16). A score of 1 refers to a slight
reaction to an auditory click stimulus and a score of 2 refers to a
freeze or inch response. In isolation, this solitary statistically signicant nding for this qualitatively subjective group difference in sensorimotor functioning was not considered to be physiologically signicant
or indicative of a meaningful difference in the pharmacology of
morphine versus hydrocodone.
During the withdrawal phase all four categorical measurements
representing the sensorimotor domain were signicantly higher in
morphine and hydrocodone treatment groups when compared to tap
water treated controls. Elevations in approach response were recorded for hydrocodone (Days 16 and 18) and morphine treated rats (Day
18). Responses to tail pinch and touch were equally affected in
hydrocodone and morphine rats on all three days of withdrawal (Days
16, 17, and 18) and elevated responses to an auditory (mechanical
clicker) stimulus were also reported on Days 1 and 3 of withdrawal in
10
the hydrocodone treated groups of rats (Days 16 and 18). When compared to their water control cohorts, these changes in reexive response
to sensorimotor stimulation (auditory, haptic, and pain sensory
systems) in the morphine and hydrocodone groups are considered to
be consistent with classic signs of opiate withdrawal in the rat.
In summary of the dependence liability assessment, there were no
physiologically signicant differences between water treated control
subjects and their selected opiate treatment group cohorts prior to dosing. The escalating dose strategy has been previously used in numerous
published reports of drug dependence induction, appearing in scientic
peer reviewed journals. This strategy was intended to allow for a
temporal dose escalation procedure based on the animal's ongoing
physiological status and the rates of ongoing normal behaviors exhibited a few hours following the rst of two daily doses. The results of the
current study conrm that such dose escalation procedures can be conducted without serious or detrimental physiological consequences in
that no biologically signicant differences were noted in morphine or
hydrocodone treated rats, compared to water treated cohorts, during
the repeat dosing procedure in which rats were receiving up to
150 mg/kg twice daily (300 mg/kg/day, Day 15 FOBs) of the two opiate
derivatives. The termination of relatively high doses of morphine
(150 mg/kg, b.i.d.) produced signs of classic opiate withdrawal
summarized in Table 1.
4. Discussion
Morphine has been generally regarded as the reference compound
against which other analgesics are assessed (World Health
Organization, 1972). From the available data, it may be concluded
that hydrocodone's abuse liability is most likely attributable to its own
intrinsic efcacy at -type opioid receptors. During the period of
November 1949 through March 1950, the Committee on Drug
Addiction and Narcotics of the National Research Council was called
upon for evaluation and recommendations concerning the efcacy
and dependence producing potential of hydrocodone and other
narcotics. Hydrocodone was reviewed to be:
in all respects morphine-like and, in spite of the chemical relationship to
codeine, closer to morphine than to codeine in its dependence liability
(Fraser & Isbell, 1950; Isbell, 1949).
The data generated in this study are consistent with these
conclusions.
According to Shannon and Holtzman (1976), the property of
morphine which enables it to function as a discriminative stimulus in
the rat is analogous to the component of action of morphine responsible
for producing the subjective effects in man. For opiates, there is a high
Table 1
Summary of clinical signs of opiate withdrawal induced by hydrocodone and morphine
following 15 days of escalating doses (40 mg/kg/day up to 300 mg/kg/day).
Functional
domain
Observation
Hydrocodone
Morphine
Activity/arousal
Ease of removal
General arousal
Handling reactivity
Rearing
Forelimb grip strength
Gait
Stereotypy
(Snifng &
grooming)
(Snifng &
grooming)
Neuromuscular
Sensorimotor
Physiological
Autonomic
Approach response
Click response
Tail pinch response
Touch response
Bodyweight
Defecation
correspondence between drugs that exert morphine-like discriminative

effects in rats and those that evoke morphine-like subjective reports in
humans (Colpaert, 1978; Shannon & Holtzman, 1977). Inasmuch as the
subjective effects of opioids play an important role in their relatively
high abuse potential (i.e. Fraser, 1968a,b; Jasinski, 1977), discrimination
procedures provide a laboratory model in which to assess the opiatelike abuse potential of other NCEs (cf. Sannerud & Young, 1987). One
of the best predictors of abuse liability of opiates is the demonstration
of similar drug discriminative generalization functions to those generated by a known and commonly abused opiate like morphine or oxycodone (Shannon & Holtzman, 1977). With reference to the drug
discrimination assay in all respects the subjective and pharmacokinetic
effects produced by hydrocodone are similar to both oxycodone and
morphine (cf Beardsley et al., 2004; Cone et al., 1978; Lelas et al.,
1999; Picker, Doty, Negus, Mattox, & Dykstra, 1990; Tomkins et al.,
1997; Yan-Hua & Ji-Wang, 2000).
The self-administration assay demonstrated reinforcing properties of
morphine, oxycodone and hydrocodone using stable operant cocaine
self-injection baselines in rats, as suggested by the FDA draft guidance
document. All three opiates initiated and maintained self-administration
over three consecutive days of substitution in rats conditioned to selfadminister 0.56 mg/kg/infusion of cocaine (Garcia-Lecumberri et al.,
2011; van Ree, Slangen, & de Wied, 1978; Weeks, 1962; Weeks & Collins,
1964, 1979; Werner, Smith, & Davis, 1976). The total amount of drug
self-delivered by the rats in this study was within the range that produced
signicant interoceptive or subjective effects equivalent to a standard
0.04 mg/kg subcutaneously administered fentanyl training dose in rats
(Meert & Vermeirsch, 2005).
The results from this study conrm the abuse liability status of
hydrocodone. Using a set of diverse behavioral assays promulgated
by the recent FDA draft guidance document, the abuse liability of
hydrocodone is demonstrated to be equivalent in all respects to the
prototypic mu opioid agonist, morphine (Beach, 1957; Blasig, Herz,
Reinhold, & Zieglgansberger, 1973; Fuentes, Hunt, & Crossland, 1978;
Mucha, Kalant, & Linseman, 1979; Schulteis, Markou, Gold, Stinus, &
Koob, 1994).
Behavioral observations in the FOB have been a component of safety
assessment studies in developmental, reproductive, and standard
toxicology since 1975 (Irwin, 1968; Ofce of Technology Assessment,
US Congress, 1990). The European Union (2009), Controlled Substances
Staff, Center for Drug Evaluation and Research CDER at the United States
Food and Drug Administration (2010), the U.S. Department of Health
and Human Services (2010), and the International Commission on
Harmonisation (M3[R2]: 2009; S7A: 2000) have adopted the FOB as
the preferred assay for the preclinical assessment of drug dependence/
withdrawal. This study further validates the utilization of this procedure
as a rst tier descriptive technique that is uniquely applicable to the
characterization of drug withdrawal (including opiate withdrawal)
states.
The use of a stimulant-based laxative over the course of chronic
opiate dosing was similar to standardized treatments of chronic pain
patients prescribed long term opiate treatments and was used in this
study for the safety and health of the animals. The laxatives demonstrated that gut motility could be effectively maintained over the course of
chronic opiate dosing regimen without affecting the quality or quantity
of withdrawal signs produced upon abrupt withdrawal. The use of the
escalating dose strategies allowed for high dose opiate exposure
(300 mg/kg/day) without concomitant decrements in behavioral function as assessed in the functional observational batteries conducted on
Day 7 and Day 15 of exposures. And nally, escalating doses from
20 mg/kg b.i.d. to 150 mg/kg b.i.d. dosing produced a series of classic
signs of opiate withdrawal in the rat consistent with those described
in the published literature appearing in peer-reviewed scientic
journals.
The data from this study clearly demonstrated an equivalent abuse
potential shared by morphine, oxycodone, and hydrocodone using
predictive behavioral assays described in the draft regulatory guidance

document issued by the US FDA.
Acknowledgments
This work was conducted and funded by MPI Research, Inc., an
independently owned Contract Research Organization that employs all
of the authors at the time of study conduct and manuscript preparation.
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JPM-06270; No of Pages 12

Journal of Pharmacological and Toxicological Methods xxx (2015) xxxxxx

Contents lists available at ScienceDirect

Journal of Pharmacological and Toxicological Methods

Abuse liability assessment of hydrocodone under current draft

2015 Elsevier Inc. All rights reserved.

primates. The results of these assays must be supplied prior to health

(i.e., Vicodin, Hycotuss), the only legitimate U.S. drug products on

2. Material and methods

protocols governing these studies had prior approval of MPI Research

the completion of the maintenance dose tests, an extinction test with

1.0 mg/kg/injection of cocaine. All ve tested doses of cocaine sustained

mu-opioid, hydrocodone engendered an inverted U-shaped function

associated with the s.c. administration of fentanyl in a standard FR10

Similarly, Fig. 5 shows the cross generalization prole for

Some calls of swelling were documented in 1 out of 16 rats in each of

position, and c) rapid respirations. None of these calls were made in

in the morphine and hydrocodone treatment groups experiencing the

successive days using an equi-effective dosing strategy to a nal dose on

3.3.3. Food consumption

During the withdrawal phase hydrocodone and morphine treated

between the treatment groups. Stereotypy calls were distributed

correspondence between drugs that exert morphine-like discriminative

predictive behavioral assays described in the draft regulatory guidance

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