Download Relative Reinforcing Effects of Three Opioids with Different

0022-3565/02/3012-698 –704$7.00
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics
JPET 301:698–704, 2002
Vol. 301, No. 2
4630/981643
Printed in U.S.A.
Relative Reinforcing Effects of Three Opioids with Different
Durations of Action
M. C. KO, J. TERNER, S. HURSH, J. H. WOODS, and G. WINGER
Departments of Pharmacology and Psychology, University of Michigan, Ann Arbor, Michigan (M.C.K., J.T., J.H.W., G.W.); Science Applications
International, Joppa, Maryland (S.H.); and Johns Hopkins University School of Medicine, Baltimore, Maryland (S.H.)
Received October 9, 2001; accepted February 6, 2002
This article is available online at http://jpet.aspetjournals.org
Relatively little is known about what properties of drugs of
abuse contribute to their reinforcing effects. It is generally acknowledged, however, that stimuli function better as reinforcers if there is relatively little delay between the response and
reinforcer delivery (Renner, 1964; de Villiers, 1977). There is
some evidence to support the notion that drugs that have fast
onsets of action are stronger reinforcers than drugs that have
slow onsets of action. Balster and Schuster (1973) and Panlilio
et al. (1998), for example, reported that lower rates of behavior
were maintained by cocaine when it was delivered slowly compared with more rapid administration. We have found that
ketamine, an NMDA antagonist with a rapid onset of action, is
as strong a reinforcer as phencyclidine, an NMDA antagonist
with a somewhat less rapid onset of action, but much stronger
as a reinforcer than dizocilpine, an NMDA antagonist with a
slow onset of action (Winger et al., 2002).
These latter three drugs vary in their durations as well as
their onsets of action, and the contribution of duration of action
to the relative reinforcing effects of drugs of abuse is not well
documented. Panlilio and Schindler (2000) are among the few
who have compared behavior maintained by shorter and longer
acting drugs. They found that the ultrashort-acting opioid
remifentanil served as a reinforcer when delivered intravenously to rats and that it maintained breakpoints under progressive ratio schedules that were not markedly different from
resulting in drug administration was increased from one session to
the next. Comparisons were made of the behavioral economic
variables Pmax and area under the demand curve (Omax). Remifentanil maintained higher rates of responding than did alfentanil, and
alfentanil maintained higher rates of responding than did fentanyl.
When normalized demand functions were compared, however,
the drugs did not differ significantly from each other in terms of
Pmax or Omax. These data agree with those of others who have
suggested that duration of action is not an important contributor
to drugs’ reinforcing strength.
those maintained by the longer-acting opioid heroin. They concluded that duration of action was independent of the ability to
serve as a reinforcer.
Drugs that act at the ␮-opioid receptor are a natural choice
for experimental procedures designed to evaluate the role of
duration of drug action on reinforcing strength. There are several ␮-opioid agonists that vary almost exclusively in their
pharmacokinetics. Fentanyl is a fairly long-acting ␮-opioid agonist, alfentanil has a nearly identical profile of activity but
with a shorter duration of action, and remifentanil is an ultrashort-acting ␮-opioid agonist, useful in surgical procedures in
which it can be administered by constant infusion (Glass et al.,
1999; Rosow, 1999). What is not certain is whether these three
drugs have similar onsets of action after i.v. administration, a
property that is critical if duration of action is to be isolated as
a variable affecting reinforcing effect. In the current study, the
onsets and durations of action of fentanyl, alfentanil, and
remifentanil were determined and compared using measures of
their ability to suppress respiration and to produce antinociception after their intravenous delivery. Their relative reinforcing
effects were then evaluated using normalized demand function
analysis as described by Hursh and Winger (1995).
Materials and Methods
Subjects
This study was supported by U.S. Public Health Service Grant DA-00254 (to
J.H.W.).
Eleven adult male and female rhesus monkeys (Macaca mulatta)
with body weights ranging between 5.4 and 12.8 kg were used. They
ABBREVIATIONS: NMDA, N-methyl-D-aspartate; Ve, minute volume of respiration; MPE, maximum possible effect; inj, injection.
698
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017
ABSTRACT
The role of duration of action on the relative reinforcing effects of
three opioid drugs (fentanyl, alfentanil, and remifentanil) was evaluated. Duration and onset of action were determined using measures of respiratory depression and antinociception after i.v. administration. Effects on minute volume of respiration indicated that
each of the three opioids had immediate onsets of action after i.v.
administration. Fentanyl’s duration of suppression of respiration
and antinociception was longer than that of alfentanil, which was
longer than that of remifentanil. Reinforcing strength was measured in i.v. self-administration studies in which the fixed ratio
Duration of Action and Opioid Reinforcement
were housed individually with free access to water and were fed
approximately 25 to 30 biscuits (Purina Monkey Chow; Ralston
Purina, St. Louis, MO) and fresh fruit daily. The animals were
maintained on a 12-h light/dark cycle. The monkeys were housed in
facilities accredited by the American Association for the Accreditation of Laboratory Animal Care, and the studies were conducted in
accordance to the Guide for the Care and Use of Laboratory Animals
as adopted and promulgated by the National Institutes of Health
(National Academy Press, Washington DC, revised 1996).
Experimental Procedures and Designs
levers were three stimulus lights: a red light on the right indicated
drug availability, a green light in the center indicated an intravenous infusion, but a third light was not used in this experiment.
The monkeys all had a history of i.v. alfentanil self-administration. They had initially been adapted to wearing a Teflon mesh jacket
attached to a flexible steel tether (Lomir Biomedical, Malone, NY).
Aseptic surgical techniques were then used to implant a silicone
catheter into one of eight major veins (external or internal jugular,
femoral, or brachial veins). The proximal end of the catheter was
inserted close to the heart, and the distal end was run subcutaneously from the incision site toward the monkey’s back, exiting at the
midscapular region. The catheter traveled through the tether to the
back of the cage where it connected to a swivel. On the outside rear
of the cage, a second section of silicone tubing connected to the back
of the swivel, and attached to a filter (Gilman Scientific, Ann Arbor,
MI) before connecting to an infusion pump (model MHRK 55;
Watson-Marlow Co., Falmouth, UK).
The experiments were controlled by IBM computers, programmed
with software from MED Associates (St. Albans, VT). These were
located in a room adjacent to the room in which the animals were
housed and tested. Two experimental sessions were scheduled each
day, one beginning at approximately 10:00 AM and the second beginning at approximately 4:00 PM. Each session was 130 min in
duration, signaled by the onset of the red stimulus light. The schedule of drug availability started at fixed ratio 10, time-out 10 s. Thus,
10 responses on the lever under the red light turned off the red light
and turned on the green light and the infusion pump. Once the
infusion was completed, all lights were extinguished for 10 s, and
responses had no programmed consequences. The red light was
illuminated again. After several sessions of drug and saline availability on this schedule, only drug was made available, and the fixed
ratio (i.e., the ratio between the number of responses and reinforcer
delivery) was increased on each consecutive session from 10 to 32 to
100 to 320 to 1000. The animal was then returned to the fixed ratio 10
time-out 10 schedule, and drug availability was again alternated with
saline availability for several sessions. The incrementing fixed ratio
procedure was then implemented again. Each dose of each drug was
tested in the incrementing fixed ratio procedure twice in each monkey.
Data Analysis
Respiration. Individual Ve values obtained in each test session
were expressed as percentage of control of the respective parameters
collected before drug administration. The volume was calculated
once per minute. For the sake of clarity, the values are plotted once
every 5 min (Fig. 1). Mean and S.E.M. values were calculated. These
data were analyzed by a two-way analysis of variance followed by the
Newman-Keuls test for multiple comparisons. In particular, the
values obtained at the time points of 1, 5, 15, 30, 45, and 60 min after
injection were compared among groups.
Antinociception. Individual tail-withdrawal latencies were converted to percentage of maximum possible effect (MPE) by the following formula: %MPE ⫽ [(test latency ⫺ control latency)/(cutoff
latency 20 s ⫺ control latency)] ⫻ 100. Comparisons were made for
the same monkeys across experimental conditions. Data were analyzed by a two-way analysis of variance followed by the NewmanKeuls test for multiple comparisons.
Self-Administration. Rates of responding were calculated as the
number of responses made in a session while the red light was
illuminated, divided by the number of seconds that the red light was
illuminated. Drug consumption was calculated as the number of
injections taken in a session multiplied by the dose of drug per
injection. The data from each animal were averaged over the two
sessions at each fixed ratio value for each drug and dose. These
means were then averaged over the three animals to produce the
results that are shown in Fig. 3.
Measures of reinforcing strength were indicated by two variables,
Pmax and Omax, that are traditionally obtained from the demand
curves. Demand curves describe the relation between consumption
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017
Respiration. Four rhesus monkeys, two males and two females,
served as subjects in this part of the study. The apparatus used was
similar to that described previously (Howell et al., 1988; France and
Woods, 1990; Butelman et al., 1993). The monkey was seated in a
restraint chair that was placed in a ventilated, sound-attenuating
chamber. A helmet was placed over the monkey’s head and sealed
around its neck by two closely fitting latex shields. Gas (air) flowed
into the helmet and was pumped out at a rate of 8 l/min. The
monkeys’ breathing produced changes in pressure inside the helmet
that were measured with a pressure transducer connected to a polygraph (Grass model 7); the data were recorded on a polygraph trace
and in a microprocessor (IBM PC jr.) via an analog-to-digital converter. The apparatus was calibrated routinely with known quantities of air.
Before the test session, a catheter (Angiocath 24-gauge/19 mm; BD
Biosciences, Franklin Lakes, NJ) was inserted in the monkey’s saphenous vein. Each opioid was given intravenously at the start of the
recording session. Four doses of fentanyl (0.0032– 0.032 mg/kg and
vehicle), four doses of alfentanil (0.0032– 0.032 mg/kg and vehicle),
and two doses of remifentanil (0.0032– 0.0056 mg/kg and vehicle)
were administered on separate sessions. Doses were increased until
at least a 50% decrease in the baseline value was produced. Each
dose was tested two times in each monkey.
Test sessions were conducted twice per week with a minimum
72-h interval between drug exposures. Experimental sessions consisted of 60 min of exposure to air. Respiratory parameters were
recorded continuously during sessions. Frequency, the number of
inspirations per minute, was directly determined. Minute volume
(Ve), the number of liters of air inspired per minute, was calculated
from integration of the polygraph tracing. Because, as has been
shown previously (Paronis and Woods, 1997; Kishioka et al., 2000),
Ve was the most sensitive measure of drug effect, the effects of the
three opioids on Ve measured during air breathing are presented
herein.
Antinociception. Four rhesus monkeys, one male and three females, served as subjects in this part of the study. The warm water
(50°C) tail-withdrawal procedure used in this study to evaluate
antinociception was similar to that described by Dykstra and Woods
(1986). Monkeys were seated in primate restraint chairs, and the
lower part of their shaved tails (approximately 15 cm) was immersed
in a thermos flask containing water maintained at either 40, 50, or
55°C. Tail-withdrawal latencies were timed manually using a microprocessor (IBM PC) via a hand-held push-button switch. Monkeys
were tested one to two times at three temperatures in a random
order. If the monkeys did not remove their tails from the flask within
20 s (cutoff), the flask was removed, and a maximum time of 20 s was
recorded. Sessions began with control determinations at each temperature. Each opioid was administered intravenously through a
saphenous vein from either side of the lower legs. Subsequent tailwithdrawal latencies were determined at 5, 15, 30, 45, 60, and 90
min after injection. A single dosing procedure was used in all test
sessions, which were conducted twice per week with a 72-h interval.
Self-Administration. Three individually housed adult rhesus
monkeys, two males and one female, were subjects in this experiment. They were housed in stainless steel cages (83.3 ⫻ 76.2 ⫻ 91.4
cm in depth). Each cage was equipped with a lever panel with two
response levers located on the right-hand side of the cage. Above the
699
700
Ko et al.
accounted for by the curve fit (R2). These were returned to the Excel
spreadsheet, where Pmax and Omax were calculated.
Response output functions were determined as well. These demonstrated the relation between the total number of responses in a
given session and the price. In these functions, the Pmax is represented as the highest point on the curve, and Omax is represented by
the total number of responses at Pmax. The response output functions
for the three drugs were established using the formula Y ⫽ log(100)
⫹ ((B ⫹ 1)) ⫺ (Aⴱ(10∧X)) 䡠 log(e), where Y is log responses and X is log
P. Initial values were the same as those for the demand function.
Statistical comparison among the Pmax and Omax values were made
with a repeated measures analysis of variance.
Drugs. Fentanyl HCl, alfentanil HCl (National Institute on Drug
Abuse, Bethesda, MD), and remifentanil (GlaxoWellcome, Research
Triangle Park, NC) were dissolved in sterile water for the respiration
and analgesia studies, and in sterile saline for the self-administration studies. For systemic administration in both respiration and
antinociception assays, each compound was administered intravenously at a volume of 0.1 ml/kg.
Fig. 1. Effects of fentanyl (top), alfentanil (middle), and remifentanil
(bottom) on Ve over time. Abscissae: time in minutes after the i.v. administration of each opioid. Ordinates: minute volume as percentage of
nondrug control. Data points are the means (⫾S.E.M.) for four monkeys.
(total drug intake per session) and price (fixed ratio value divided by
dose in mg/kg/inj). Pmax is a measure of the elasticity of the demand
function, indicating how quickly reinforced behavior decreases as the
price of the reinforcer is increased. Omax reflects the amount of
behavior that the reinforcer maintains.
Because the three opioids could vary in their potency as reinforcers, direct comparisons of their consumption versus fixed ratio would
be confounded by these potency differences. We therefore used a
normalization procedure described by Hursh and Winger (1995) to
generate the demand curves. This procedure sets the consumption of
each of the drugs at the lowest price (highest dose at the lowest fixed
ratio) to the same normalized value of 100, and compares the elasticity and Omax values of the curves that have the same origin.
Normalized demand curves were constructed after determination of
the values of normalized dose or 100/number of reinforcers earned at
the lowest price (q), normalized price: fixed ratio/q (P), and normalized consumption: number of reinforcers per session at each fixed
ratio 䡠 q) (Q). Log P and log Q were calculated in an Excel spreadsheet
from the consumption data for each dose, averaged across monkeys.
This information was graphed in GraphPad Prism (GraphPad Software, San Diego, CA) by using nonlinear curve fitting and the formula Y ⫽ log(100) ⫹ B(X) ⫺ (A 䡠 (10∧X)) 䡠 log(e), where Y is log Q and
X is log P. Initial values were set to a ⫽ ⫺0.05 and b ⫽ 0.004. Prism
returned values for b (initial slope), a (acceleration), and variance
Respiration. The effects of fentanyl, alfentanil, and
remifentanil on Ve, measured immediately after and for 60
min after intravenous administration, are shown in Fig. 1.
Effective doses of each drug depressed respiration as quickly
as measurements could be taken (at 1 min). Fentanyl produced a dose-related depression of Ve that was 43 ⫾ 6% of
control at a dose of 0.032 mg/kg [F(4,28) ⫽ 20.1; p ⬍ 0.01] at
1 min and recovered to 65 ⫾ 5% of control at the 60-min
measurement period (p ⬍ 0.01). Alfentanil also produced a
dose-related suppression of Ve to a maximum of 32 ⫾ 4% of
control [F(4,28) ⫽ 18.8; p ⬍ 0.01] at 1 min. Alfentanil was
equipotent with fentanyl, also producing the maximum response at a dose of 0.032 mg/kg (p ⬍ 0.01). Alfentanil’s action
on minute volume had returned to control levels by approximately 30 min after intravenous administration of 0.032
mg/kg (p ⬍ 0.01). Remifentanil was also effective in suppressing Ve. Although a dose of 0.0032 mg/kg had little effect on
Ve, a dose of 0.0056 mg/kg produced a 47 ⫾ 7% reduction in
Ve (p ⬍ 0.01) at 1 min; the animals were breathing at a
normal volume within 10 min of drug administration
[F(5,35) ⫽ 6.9; p ⬍ 0.01].
Antinociception. The antinociceptive effects of fentanyl,
alfentanil, and remifentanil measured in 50°C water are
shown in Fig. 2. There was no change in the response to 40°C
water, and the effects using 55°C water were much the same
as those shown herein with 50°C water. Each of the opioids
produced dose-dependent thermal antinociception at this
temperature. Fentanyl and alfentanil were equipotent and
equieffective. At a dose of 0.032 mg/kg, both drugs produced
respiratory arrest in two monkeys, which was reversed by an
opioid antagonist (data not shown). At smaller doses (0.018
and 0.01 mg/kg) the antinociceptive effects of these drugs and
their durations of action were dose-dependent (fentanyl
[F(3,9) ⫽ 59.7; p ⬍ 0.01] and alfentanil [F(3,9) ⫽ 140.9; p ⬍
0.01]. In particular, 0.018 mg/kg fentanyl produced significant antinociception that lasted for 60 min (p ⬍ 0.01). The
antinociception produced by alfentanil at this dose lasted for
approximately 15 min (p ⬍ 0.01). Remifentanil produced
thermal antinociception only at a dose of 0.0056 mg/kg, and
this maximal effect was very transient, lasting less than 15
min. Significant differences in antinociceptive effects be-
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017
Results
Duration of Action and Opioid Reinforcement
701
Fig. 2. Effects of fentanyl (top), alfentanil (middle), and remifentanil
(bottom) on thermal analgesia by using 50°C water. Abscissae: time in
minutes after the i.v. administration of each opioid. Ordinates: latency to
withdraw the tail, as a percentage of the maximum possible effect. Data
points are the means (⫾S.E.M.) for four monkeys.
tween the dose and vehicle condition are shown at corresponding time points in Fig. 2.
Self-Administration. The average rates of responding
maintained by each of the three opioids, and the session
intakes resulting from the injection-contingent responding
are shown in Fig. 3, left. The fastest rates of responding were
produced by remifentanil, with a dose of 0.0001 mg/kg/inj
producing an average maximum rate of 1.9 responses/s at
fixed ratio 32. Alfentanil maintained the next fastest rate of
1.32 responses/s at fixed ratio 32. Fentanyl maintained the
slowest rates, with a maximum rate of 0.94 responses/s at a
dose of 0.001 mg/kg/inj and fixed ratio 1000. In general, rates
of responding increased as the fixed ratio value was increased up to a maximum, and then decreased with further
increases in fixed ratio value, producing an inverted
U-shaped function of response rate against fixed ratio value.
For the largest dose of fentanyl, rates increased monotonically across the fixed ratio values, although downturns would
certainly have been observed at higher ratio values.
Typically, as the dose of each opioid was increased, the
fixed ratio at which the maximum rate of responding oc-
Discussion
The effects of these three ␮-opioids on respiration and
antinociception assays confirm in rhesus monkeys what is
commonly held in clinical practice: fentanyl was longer acting than alfentanil, which was longer acting than remifentanil (Scholz et al., 1996; Rosow, 1999; Gesztesi et al., 2000).
In addition, fentanyl and alfentanil were nearly equally potent, and remifentanil was approximately 6 times more potent. After intravenous administration, each of these opioids
had immediate onsets of action and a qualitatively similar
ability to suppress respiration and to produce antinociception. These observations are consistent with the pharmacological profiles of ␮-opioid full agonists (Niemegeers and
Janssen, 1981; James et al., 1991; Glass et al., 1993; Willens
and Myslinski, 1993; Emmerson et al., 1996).
In measures of reinforcing effects, the same order of potency was seen as in measures of respiration and antinociception: fentanyl and alfentanil were nearly equipotent and
remifentanil was 10 times more potent. The inverted Ushaped curves that developed as fixed ratio values were increased across each dose of drug have been observed in other
studies in which fixed ratio values are increased systematically (Lemaire and Meisch, 1985; Winger, 1993). The relatively low rates of responding that occurred with small ratio
values was likely to be due to accumulation of drug and
consequent drug-induced suppression of ongoing rates of re-
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017
curred increased as well. Thus, with fentanyl, a dose of
0.0001 mg/kg/inj maintained peak response rates at fixed
ratio 32, a dose of 0.0003 mg/kg/inj maintained peak response
rates at fixed ratio 100, and a dose of 0.001 mg/kg/inj maintained peak response rates at fixed ratio 1000; the rates
maintained by this largest dose could have increased if
higher ratios had been evaluated. Similarly, with alfentanil
the smallest dose of 0.0003 mg/kg/inj maintained peak response rates at fixed ratio 32, the intermediate dose of 0.001
mg/kg/inj maintained peak response rates at fixed ratio 100,
and the largest dose of 0.003 mg/kg/inj maintained peak
response rates at fixed ratio 320. The one exception was
remifentanil for which the two smaller doses both produced
peak response rates at a fixed ratio 32, and the largest dose
maintained peak response rates at fixed ratio 320.
The number of injections and the amount of drug consumed decreased monotonically as the fixed ratio value increased (Fig. 3, right). The larger the dose per injection, the
greater the total session consumption across fixed ratio values.
The demand and response-output functions are shown for
individual animals in Fig. 4. Typical demand functions developed in which consumption was maintained across low
price increases, and decreased as price became larger (Fig. 4,
left). The goodness of fit for the demand curves to the averaged data was excellent; R2 values were 0.98 for alfentanil
and remifentanil and 0.93 for fentanyl. The Pmax and Omax
values, obtained using averages across monkeys, are shown
in the figure and were, respectively, 528 and 13,145 for
remifentanil, 365 and 9953 for alfentanil, and 383 and 6888
for fentanyl. There were no statistically significant differences among either the Pmax or Omax values, indicating that
these three opioids did not differ significantly in their reinforcing effectiveness.
702
Ko et al.
sponding. Drug accumulation was greater at small ratio values because these small values resulted in shorter interinjection times. As the ratio was increased, interinjection times
increased, drug accumulation was reduced, and rates rose as
a consequence. The relatively low rates of responding that
occurred at higher ratio values were likely due to an entirely
different mechanism, one of more relevance to the comparison of relatively reinforcing strength: these low rates are
presumed to be a function of the inability of the drug to
maintain responding as the amount of behavior necessary to
obtain the drug was increased. Larger doses of drug were
more resistant to the ratio increases, indicating that larger
doses functioned better as reinforcers than smaller doses.
Despite the increases in rates that accompanied initial
increases in fixed ratio values, there was a monotonic decrease in total session consumption for all drugs as the fixed
ratio values increased. In addition, the total consumption
was consistently greater as the dose per injection of each of
the drugs increased.
The demand functions generated indicated that consumption of these drugs was defended as price (ratio/dose)
was initially increased. Eventually, however, a price was
reached at which drug intake began to decrease. This price
at which the demand curve changed from relatively inelas-
tic to relatively elastic (slope of the curve ⫽ ⫺1) is known
as the Pmax and reflected the amount of behavior the
monkeys were willing to expend to obtain the drugs as the
price increased. The Pmax values, normalized to account for
differences in potency among the drugs, did not differentiate the drugs, indicating that these opioids did not differ
in their ability to maintain behavior in the face of increasing response requirements. A second measure of reinforcing effectiveness is Omax, the total responses at Pmax. The
Omax reflected the total amount of behavior the animals
were willing to expend to obtain the drugs. Normalized
Omax values also did not differ significantly among the
three opioids, supporting the notion that the drugs did not
differ in their reinforcing effectiveness. Therefore, insofar
as reinforcing strength after i.v. delivery plays a role in
drug abuse potential in humans, these drugs should not be
expected to have different abuse potentials.
The relation between the measures of Pmax and Omax is not
yet well defined. Bickel et al. (2000) recently described reinforcing effectiveness as being heterogenous, with Pmax and
Omax each contributing separately to the concept. Our previous data (Hursh and Winger, 1995) suggested that these two
indices may vary independently. Why a particular reinforcer
might, for example, resist increases in price but not produce
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017
Fig. 3. Rates of responding (left) and consumption (right)
of the three opioids, as a function of fixed ratio values.
Data for rates of responding are shown as responses per
second for fentanyl (top), alfentanil (middle), and
remifentanil (bottom). Abscissae: number of lever-press
responses during the red stimulus light condition. Ordinates: number of responses required for delivery of each
reinforcer. Data for consumption are shown as milligrams per kilogram per session (abscissae) for the drugs
as a function of the fixed ratio value (ordinates). Data
points are the means (⫾S.E.M.) for three monkeys.
Duration of Action and Opioid Reinforcement
703
large amounts of behavior relative to another reinforcer remains unknown. Fortunately, for the three drugs evaluated
herein, the differences among the Pmax and Omax values were
small and not significant, presenting consistent evidence
that these drugs do not differ in their reinforcing effectiveness.
In conclusion, remifentanil, alfentanil, and fentanyl had
similar rapid rates of onset of action, and differed exclusively in their potencies and durations of action. Despite
the fact that, compared with alfentanil, remifentanil maintained relatively higher rates of responding, and fentanyl
maintained relatively lower rates of responding, none
these drugs differed greatly in their elasticities or total
response outputs, indicating similar apparent reinforcing
strengths. Although it must be kept in mind that only
three drugs were studied, and that these drugs had durations of action that spanned a relatively narrow range
(15– 60 min), the data support the report of Panlilio and
Schindler (2000) that duration of action does not appear to
play an important role in determining the reinforcing
strength of drugs that are otherwise the same with respect
to onset of action and quality of effect.
Acknowledgments
We thank Debbie Huntzinger, Laurie McDowell, Mark Johnson,
Michael Song, and John Busenbark for excellent technical assistance.
References
Balster RL and Schuster CR (1973) Fixed-interval schedule of cocaine reinforcement:
effect of dose and infusion duration. J Exp Anal Behav 20:119 –129.
Bickel WK, Marsch LA, and Carroll ME (2000) Deconstructing relative reinforcing
efficacy and situating the measures of pharmacological reinforcement with behavioral economics: a theoretical proposal. Psychopharmacology 153:44 –56.
Butelman ER, France CP, and Woods JH (1993) Apparent pA2 analysis on the
respiratory depressant effects of alfentanil, etonitazene, ethylketocyclazocine
(EKC) and Mr2033 in rhesus monkeys. J Pharmacol Exp Ther 264:145–151.
de Villiers P (1977) Choice in concurrent schedules and a quantitative formulation of
the law of effect, in Handbook of Operant Behavior (Honig WK and Staddon JER
eds) pp 233–287, Prentice-Hall, Englewood Cliffs, NJ.
Dykstra LA and Woods JH (1986) A tail withdrawal procedure for assessing analgesic activity in rhesus monkeys. J Pharmacol Methods 15:263–269.
Emmerson PJ, Clark MJ, Mansour A, Akil H, Woods JH, and Medzihradsky F (1996)
Characterization of opioid agonist efficacy in a C6 glioma cell line expressing the
␮ opioid receptor. J Pharmacol Exp Ther 278:1121–1127.
France CP and Woods JH (1990) Respiratory effects of receptor-selective opioids in
rhesus monkey, in The International Narcotics Research Conference (INRC) ‘89
(Quirion R, Jhamanda K, and Gianoulakis C eds) pp 295–298, A. R. Liss, New
York.
Gesztesi Z, Rego MM, and White PF (2000) The comparative effectiveness of fentanyl
and its newer analogs during extracorporeal shock wave lithotripsy under monitored anesthesia care. Anesth Analg 90:567–570.
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017
Fig. 4. Demand curves (left) and
response output functions (right)
for the individual opioids. Left abscissae: log of the normalized price;
left ordinates: log of the normalized
consumption. Right abscissae: log
of the normalized price; right ordinates: log of the total responses.
Data points are the averages for
each of the three individual monkeys at each of the three tested
doses. The Pmax and Omax data (left)
were determined using the averaged values for the demand functions.
704
Ko et al.
Glass PS, Gan TJ, and Howell S (1999) A review of the pharmacokinetics and
pharmacodynamics of remifentanil. Anesth Analg 89:S7–S14.
Glass PS, Hardman D, Kamiyama Y, Quill TJ, Marton G, Donn KH, Grosse CM, and
Hermann D (1993) Preliminary pharmacokinetics and pharmacodynamics of an
ultra-short-acting opioid: remifentanil (GI87084B). Anesth Analg 77:1031–1040.
Howell LL, Bergman J, and Morse WH (1988) Effects of levorphanol and several
kappa-selective opioids on respiration and behavior in rhesus monkeys. J Pharmacol Exp Ther 245:354 –372.
Hursh SR and Winger G (1995) Normalized demand for drugs and other reinforcers.
J Exp Anal Behav 64:373–384.
James MK, Feldman PL, Schuster SV, Bilotta JM, Brackeen MF, and Leighton HJ
(1991) Opioid receptor activity of GI 87084B, a novel ultra-short acting analgesic,
in isolated tissues. J Pharmacol Exp Ther 259:712–718.
Kishioka S, Paronis CA, Lewis JW, and Woods JH (2000) Buprenorphine and
methoclocinnamox: agonist and antagonist effects on respiratory function in rhesus monkeys. Eur J Pharmacol 391:289 –297.
Lemaire GA and Meisch RA (1985) Oral drug self-administration in rhesus monkeys:
interactions between drug amount and fixed ratio size. J Exp Anal Behav 44:377–
389.
Niemegeers CJE and Janssen PAJ (1981) Alfentanil (R39209), a particularly shortacting morphine-like narcotic for intravenous use in anesthesia. Drug Dev Res
1:83– 88.
Panlilio LV, Goldberg SR, Gilman JP, Jufer R, Cone EJ, and Schindler CW (1998)
Effects of delivery rate and non-contingent infusions of cocaine on cocaine selfadministration in rhesus monkeys. Psychopharmacology 137:253–258.
Panlilio LV and Schindler CW (2000) Self-administration of remifentanil, an ultrashort acting opioid, under continuous and progressive ratio schedules of reinforcement in rats. Psychopharmacology 150:61– 66.
Paronis CA and Woods JH (1997) Ventilation in morphine-maintained rhesus monkeys. II: Tolerance to the antinociceptive but not the ventilatory effects of morphine. J Pharmacol Exp Ther 282:355–362.
Renner KE (1964) Delay of reinforcement: a historical review. Psychol Bull 61:341–
361.
Rosow CE (1999) An overview of remifentanil. Anesth Analg 89:S1–S3.
Scholz J, Steinfath M, and Schulz M (1996) Clinical pharmacokinetics of alfentanil,
fentanyl and sufentanil. An update. Clin Pharmacokinet 31:275–292.
Willens JS and Myslinski NR (1993) Pharmacodynamics, pharmacokinetics, and
clinical uses of fentanyl, sufentanil, and alfentanil. Heart Lung 22:239 –251.
Winger G (1993) Fixed ratio and time out changes on behavior maintained by cocaine
or methohexital in rhesus monkeys. 1. Comparison of reinforcing strength. Exp
Clin Psychopharmacol 1:142–153.
Winger G, Hursh SR, Casey KL, and Woods JH (2002) Relative reinforcing effects of
three NMDA antagonists with different onsets of action. J Pharmacol Exp Ther
301:690 – 697.
Address correspondence to: Dr. Gail Winger, Department of Pharmacology,
University of Michigan Medical School, 1301 MSRB III, Ann Arbor, MI 481090632. E-mail: [email protected]
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 4, 2017