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Vol. 289, Issue 3, 1454-1464, June 1999
Department of Anesthesia and Critical Care, The University of Chicago, Chicago, Illinois
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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The subjective, psychomotor, and physiological effects of three opioid µ-receptor agonists were studied in healthy volunteers using a cumulative-dosing procedure. Sixteen volunteers with no history of drug abuse received i.v. injections of saline (SAL), morphine (MOR), hydromorphone (HM), or meperidine (MEP) in a randomized double-blind crossover design. Subjects received 1 injection/h for the first 4 h, and a 3-h recovery period followed. SAL was injected first during each session, then SAL or increasing doses of each drug were administered every hour for the next 3 h. The absolute doses per injection were MOR: 2.5, 5, and 10 mg/70 kg; HM: 0.33, 0.65, and 1.3 mg/70 kg; and MEP: 17.5, 35, and 70 mg/70 kg. These injections resulted in cumulative doses of MOR: 2.5, 7.5, and 17.5; HM: 0.33, 0.98, and 2.28; and MEP: 17.5, 52.5, and 122.5 mg/70 kg. Subjects completed mood forms and psychomotor tests, and physiological measures were recorded at various times after each injection and during recovery. MEP tended to produce the most intense effects immediately after drug injection, which dissipated rapidly. MOR produced the mildest effects but was associated with unpleasant side effects during recovery and after the session. HM's effects were stronger than MOR's, and the recovery from HM was slower than with MEP. None of the opioids produced consistent effects that are typically associated with abuse liability. Orderly dose-response functions suggested that our cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects within the same study.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Research
in our laboratory has sought to characterize the subjective,
psychomotor, and physiological effects of opioids in healthy, normal
volunteers with no history of drug abuse (Zacny et al., 1992
; 1993;
1994a, b; 1997a, b; 1998). Through randomized, double-blind,
placebo-controlled crossover designs, dose-response curves have been
constructed that include doses of opioids that are typically prescribed
for pain relief. We have characterized the subjective, psychomotor, and
physiological effects of a variety of opioid agonists [morphine (MOR),
codeine, meperidine (MEP), fentanyl] and opioids with mixed actions
(buprenorphine, butorphanol, nalbuphine, pentazocine) in different
studies. These studies consisted of four to five sessions in which a
placebo and different doses of the opioid were tested, one dose per
session. This single-dosing method allows the effects of a range of
doses of one drug to be studied within the same individual. However,
the method does not easily allow for dose-response curves to be
constructed for multiple drugs within the same subjects because a
single-dosing study would require numerous sessions to test a range of
doses of three or four drugs. Because we administer opioids no more
than once per week, such a study would require months to conduct, and
subject recruitment and retention would be problematic. In addition,
the ethics of exposing healthy volunteers to different opioids on many
occasions are questionable.
In the present study we sought to characterize the effects of a range
of doses of three full µ agonists, MOR, hydromorphone (HM), and MEP,
within the same subjects using a cumulative-dosing procedure.
Cumulative dosing allows the effects of different doses of a drug to be
assessed within the same session. First, the effects of a small dose
are assessed early in the session. Then more drug is added periodically
to determine the effects of larger doses (cumulative doses, or total
amount of drug administered up to that point). This procedure allows an
entire dose-response curve to be constructed in one session. By using
this procedure, dose-response curves can be determined for several
different drugs (plus placebo) within the same subjects in one study.
Cumulative dosing has been used for many years in behavioral
pharmacology to generate dose-response functions rapidly in both
nonhumans (Wenger, 1980; Winger et al., 1989) and humans (de Wit et
al., 1989; Preston and Bigelow, 1993). Besides the efficiency of the
procedure, another advantage is that even though multiple doses of each
drug are examined within the same subject, the amount of time subjects
are under the influence of each drug is much less than if subjects
received single weekly injections of each dose of opioid tested.
The present study examined mood, psychomotor, and physiological effects
of MOR, HM, and MEP in healthy volunteers with no history of drug
abuse. These opioids are commonly prescribed for pain relief, and
although each acts predominantly at the µ receptor, they may produce
somewhat different profiles of effects (Reisine and Pasternak, 1996).
Single-dosing studies conducted in our laboratory showed that i.v.
doses of MEP (17.5-70 mg/70 kg) had more intense effects on mood
(e.g., increased ratings of "sedated", "high", "coasting or
spaced out") than did MOR (2.5-10 mg/70 kg). Inter- and intrasubject
variability in ratings of drug liking was observed with both drugs:
both produced ratings indicative of liking, disliking, and neutrality
in different subjects and, to some extent, within the same subjects at
different time points. Both opioids had mild effects on
cognitive/psychomotor performance (Zacny et al., 1993, 1994a). In one
of two studies examining HM effects in healthy volunteers, oral HM
(1-6 mg/70 kg) did not significantly affect self-reported sedation,
stimulation, or strength or liking of the drug effect (Oliveto et al.,
1994). These doses did not impair performance on the Digit Symbol
Substitution Test (DSST), and in another study oral HM (1 and 3 mg)
produced mild performance impairment on only 1 of 14 measures of
cognitive/psychomotor performance (Pickworth et al., 1997).
Our goals in the present experiment were to systematically replicate our previous studies with MOR and MEP by testing the effects of a range of doses of each opioid within the same subjects and determine the viability of our cumulative-dosing procedure as an efficient way of determining dose-response functions. We included HM because, like MOR and MEP, it is a µ agonist that is commonly prescribed for pain relief.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Subjects
Candidates who consumed at least one alcoholic drink per week
were screened by a member of our research personnel. Candidates completed the SCL-90, a questionnaire designed to assess psychiatric symptomatology (Derogatis et al., 1973), the Michigan Alcoholism Screening Test (Selzer, 1971), and a health questionnaire designed to
determine medical, psychiatric, and drug-use history. Subjects were
excluded if they had any medical problems or a history of Axis-I
psychiatric disorders, including drug- or alcohol-related problems, as
defined by the Diagnostic and Statistical Manual of Mental Disorders-IV
(American Psychiatric Association, 1994).
Six female and ten male healthy volunteers [mean age (range) = 25 (21-32) years] participated. Volunteers reported consuming an average of three alcoholic drinks per week (range: 1-10 drinks). Four volunteers currently smoked marijuana (mean = 1 cigarette/week). Nine volunteers reported prior use of cannabinoids, two volunteers had used stimulants [amphetamine (AMP), methamphetamine], three volunteers reported use of hallucinogens [lysergic acid diethylamide (LSD), psylocibin], and one volunteer had used nitrous oxide recreationally. Regarding lifetime use of opioids, six volunteers reported use of prescribed opioids (codeine, hydrocodone, oxycodone), and four more had been prescribed "painkillers", the classes or names of which they could not report.
Subjects signed a written consent form that described the study in detail. The consent form stated that the drugs to be used in the study were drugs commonly used in medical settings and could come from one of six classes: sedative, stimulant, opiate, general anesthetic (at subanesthetic doses), alcohol, or placebo. Subjects underwent a resting-state electrocardiogram and a medical examination and were excluded if they had experienced any adverse reactions to general anesthetics or had pulmonary, renal, hepatic, or cardiac disorders. Urine samples were analyzed by the Cloned Enzyme Donor Immunoassay Technique (Boehringer Mannheim Corp., Indianapolis, IN) for the presence of acetaminophen, alcohol, AMPs, barbiturates, benzodiazepines, cocaine metabolites, opiates, phencyclidine, and salicylates. Subjects were told not to consume any drugs, including prescription and over-the-counter medication, for 24 h before each session. Urine samples and blood-alcohol levels (as measured by a breath intoximeter) collected before each session ensured drug and alcohol abstinence. Subjects practiced mood and psychomotor tests during an orientation session. Payment was made at a debriefing session and the study was approved by the local Institutional Review Board.
Procedure
Experimental Design.
A randomized, placebo-controlled,
double-blind crossover trial was conducted. Subjects participated in
four sessions spaced at least 1 week apart. Sessions were approximately
7.5 h in duration. During each session subjects received absolute
doses (actual amount of drug injected) of i.v. MOR (0, 2.5, 5, and 10 mg/70 kg), HM (0, 0.33, 0.65, and 1.3 mg/70 kg), MEP (0, 17.5, 35, and
70 mg/70 kg), or saline (SAL; placebo). The cumulative doses of opioid, therefore, were MOR (0, 2.5, 7.5, and 17.5 mg/70 kg), HM (0, 0.33, 0.98, and 2.28 mg/70 kg), and MEP (0, 17.5, 52.5, and 122.5 mg/70 kg).
The doses are clinically relevant: the largest absolute amount injected
was a dose that typically would be prescribed for postoperative pain
relief, and the smaller absolute doses were one-half and one-fourth
this dose. The doses, therefore, are considered equianalgesic, and
because all three opioids have similar onsets, durations, and peaks of
effects (Jaffe and Martin, 1990; Medical Economics Data Production,
1996; Reisine and Pasternak, 1996), identical injection regimens could
be used for all drugs. The drugs were drawn up by one anesthetist and
injected by another. The experimenter and anesthetist administering the
drug were aware of the drugs under study but were blind to the actual
drug being administered each session.
Experimental Sessions. The experiment took place in a departmental laboratory. Subjects were instructed not to eat food or drink nonclear liquids for 4 h before the start of the session, not to drink clear liquids for 2 h before the session, and not to use any drugs (including alcohol and medication, but excluding normal amounts of caffeine and nicotine) for 24 h before the session. Subjects delivered a urine sample for toxicology screening, and females delivered a urine sample for a pregnancy test. A breath-alcohol test was performed, and subjects signed a form that stated that they had complied with the eating, drinking, and drug restrictions described above. Subjects reclined in a semirecumbent position in a hospital bed (thus movement in the present study was minimal) and an anesthetist inserted an angiocatheter into a forearm or hand vein in the subject's nondominant arm. Subjects wore a pulse oximeter on their nondominant arm. Blood pressure (cuff attached to dominant arm) and respiration rate were measured periodically, and heart rate and arterial oxygen saturation were monitored continuously. Subjects filled out mood forms and completed psychomotor tests before drug administration and vital signs were recorded. After this baseline (BL) period subjects were told, "The injection you are about to receive may or may not contain a drug", and the anesthetist injected SAL through the angiocatheter. At various times after drug injection, mood, psychomotor performance, and physiological status were assessed. One hour after the first (SAL) injection, subjects received another injection containing the smallest drug dose (or SAL during the placebo session). Again, subjects completed mood forms and psychomotor tests, and vital signs were recorded. Subjects received two more injections in this way, with the medium and largest dose (or SAL) being injected 2 and 3 h, respectively, after the first SAL injection. Mood, psychomotor performance, and physiological status continued to be assessed for 4 h after the last injection.
Drinking water was permitted 90 min after the last injection, and lunch was provided to the subjects 2 h after the last injection. When no tests were scheduled subjects were free to engage in sedentary recreational activities, such as reading, listening to music, and watching TV, but studying was not permitted. Social interaction was possible (e.g., the subject could converse with the research technician), but subjects generally engaged in solitary activities during sessions. Subjects were transported home after sessions via a livery service with instructions not to engage in certain activities (e.g., driving, cooking, caring for children, drinking alcohol) for 12 h after the session.Dependent Measures
The first injection was administered at 0 min. The timer was started after the first injection and subsequent injections were given at 60, 120, and 180 min. All dependent measures (except the postsession adjective checklist) were completed at BL (after the angiocatheter was inserted but before the first injection) and 30 min after each injection (i.e., at 30, 90, 150, and 210 min). Subjects did not have access to how they responded on previous tests and were asked to respond to mood questionnaires "according to how you feel right now". Table 1 lists the order of testing, which remained invariant across subjects and sessions.
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Subjective Effects.
1. The Addiction Research Center
Inventory (ARCI) is a true-false questionnaire designed to
differentiate among classes of psychoactive drugs (Haertzen, 1966). A
computerized short form of the ARCI was used (Martin et al., 1971). It
had 49 items and yielded scores for five different scales:
pentobarbital-chlorpromazine-alcohol group (PCAG), sensitive to
sedative effects; benzedrine group (BG) and AMP, sensitive to AMP-like
effects; LSD, sensitive to somatic and dysphoric effects; and
MOR-benzedrine group (MBG), sensitive to euphoric effects.
) and a list reported as
sensitive to the somatic and subjective effects of opiates (Preston et
al., 1989). The checklist consisted of 12 items that were rated on a
scale from 0 ("not at all") to 4 ("extremely"). The items were
as follows: "flushing", "skin itchy", "sweating",
"turning of stomach", "numb", "dry mouth", "drive (motivated)", "carefree", "good mood", "headache",
"nodding", and "vomiting". In addition to the time points
listed above, the OAC was also administered 5, 15, and 55 min after
each injection (i.e., at 5, 15, 55, 65, 75, 115, 125, 135, 175, 185, 195, and 235 min) and every 30 min during recovery (i.e., at 270, 300, 330, 360, 390, and 420 min).
3. A locally developed visual analog scale (VAS) consisted of 23 100-mm
lines, each labeled with an adjective. Subjects were instructed to draw
a vertical mark on each line indicating how they felt at the time,
ranging from 0 mm ("not at all") to 100 mm ("extremely"). The
adjectives were as follows: "stimulated (energetic)", "high
(`drug' high)", "floating", "sedated (calm, tranquil)",
"lightheaded", "tingling", "confused", "drunk",
"elated (very happy)", "nauseous", "dizzy", "coasting
(`spaced out')", "feel good", "feel bad", "having
pleasant thoughts", "having unpleasant thoughts", "having
pleasant bodily sensations", "having unpleasant bodily
sensations", "heavy or sluggish feeling", "down (depressed)", "difficulty concentrating", "hungry", and "sleepy (drowsy,
tired)". The VAS was administered at the same time points as the OAC
(see above).
4. The Drug Effect/Liking (DEL) questionnaire assessed the extent to
which subjects currently felt a drug effect and how much they liked or
disliked the effect. Intensity of drug effect was rated on a scale of 1 to 5 (1 = "I feel no effect from it at all"; 2 = "I
think I feel a mild effect, but I'm not sure"; 3 = "I
definitely feel an effect, but it is not real strong"; 4 = "I
feel a strong effect"; 5 = "I feel a very strong effect").
For the measure of drug liking, subjects placed a vertical mark on a
100-mm line indicating how much they liked or disliked the drug (0 mm = "dislike a lot", 50 mm = "neutral", 100 mm = "like a lot"). The DEL questionnaire was administered at the same
time points as the OAC and VAS.
5. Subjects were given a postsession adjective checklist to take home
and were asked to complete this questionnaire 24 h after leaving
the laboratory. The checklist consisted of 17 symptoms, and subjects
were asked to rate each on a scale from 0 ("not at all") to 4 ("extremely") according to how much they had experienced the
symptoms in the last 24 h. The symptoms were as follows: "skin itchy", "headache", "nausea", "dry mouth", "excessive
hunger", "excessive thirst", "heavy or sluggish feeling",
"lightheaded", "confused", "down (depressed)",
"anxious", "clumsy", "coasting (`spaced out')",
"difficulty concentrating", "feel good", "feel bad", and
"vomiting".
Psychomotor/Cognitive Performance.
The following tests were
chosen because they have been used in previous opioid studies,
and the specific aspects of psychomotor/cognitive performance the
tests were designed to measure can be affected by opioids (Zacny,
1995).
), cause
extraocular muscles of the eye to diverge (exophoria); this divergence
is considered to be an indicator of psychomotor impairment
(Hannington-Kiff, 1970).
2. An eye-hand coordination test required the subject to track a
randomly moving target (a circle) on the computer screen using a
computer mouse (Nuotto and Korttila, 1991). The object of this test is
to keep a small cross, which is controlled by the mouse, inside the
moving target circle at all times as the circle moves randomly around
the screen. The length of the test was 1 min. The dependent measure was
the number of mistakes (i.e., number of times the distance from the
cross to the center of the target circle exceeded 1 cm).
3. An auditory-reaction test measured the time required for subjects to
react to an auditory stimulus (Nuotto and Korttila, 1991). Ten 50-dBA
computer-generated tones were delivered at random time intervals (1-10
s) in a 1-min time period. The tone remained on until subjects
depressed the spacebar on the computer keyboard or until 2 s
elapsed, whichever occurred first. The mean reaction time (in seconds)
was the dependent measure.
4. A logical-reasoning test measured such cognitive processes as
reasoning, logic, and verbal ability. The 1-min computerized test is
similar to that of the Logical Reasoning Test developed by Baddeley
(1968) except for test duration (1 min versus 3 min) and presentation
medium (computer versus paper and pencil). The logical-reasoning test
uses five grammatical transformations (e.g., true versus false
statements, use of the verb "precedes" versus the verb
"follows") on statements about the relationship between two
letters, A and B (e.g., A is preceded by B-true or false). The
subject's task was to respond "True" or "False" depending on
the veracity of the statement, by depressing the 1 or 0 keys, which
corresponded to true and false, respectively, on the number pad. The
number of statements answered correctly was the dependent measure.
5. In the DSST (Wechsler, 1958), subjects replaced a number with a
corresponding symbol. The paper and pencil test was timed for 1 min,
and the dependent measure was the number of symbols drawn correctly.
This test evaluates changes in information-processing performance and
the ability to concentrate. The DSST was administered at the same time
points as the OAC and VAS.
Physiological Measures. Five physiological measures were assessed: heart rate, blood pressure, arterial oxygen saturation, respiration rate, and miosis. Heart rate, blood pressure, and arterial oxygen saturation were measured noninvasively with a Cardiocap II monitor (Datex, Tewksbury, MA). Respiration rate was assessed by the research technician who was blind to the drug being administered. The number of times the subject's chest or stomach rose and fell in 30 s was counted; this number was multiplied by 2 to get breaths per min. Miosis, or pupil constriction, is a physiological marker of opioid effects and was measured by photographing the subject's right pupil in a dimly lit room and measuring the diameter of the pupil. The pupil of one subject could not be measured in some photographs; therefore, data for miosis are from 15 subjects. In addition to the time points listed above, heart rate, blood pressure, arterial oxygen saturation, and respiration rate were recorded every 30 min during recovery (i.e., at 270, 300, 330, 360, 390, and 420 min).
Data analysis
Repeated-measures ANOVA was used for statistical treatment of the data. The means for each condition were analyzed using the factors Drug (MOR, HM, MEP, or SAL) and Time (except for the postsession questionnaire for which Drug was the only factor). Mean peak (maximum) and trough (minimum) ratings were also analyzed with repeated-measures ANOVA using Drug as the factor; BL data were excluded from this analysis. F values were considered statistically significant for p < .05 with adjustments of within-factors degrees of freedom (Huynh-Feldt) to protect against violations of symmetry. When significant Drug effects were obtained, Tukey post hoc testing compared the means for each condition with the others. When significant Drug × Time effects were obtained, Tukey post hoc testing compared the means for each condition with the other means at each time point.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Subjective Effects
ARCI.
Figure 1 shows that the
three active drugs produced dose-related increases in scores on the
PCAG (Drug × Time: p < .001, top) and LSD
(Drug × Time: p < .001, middle) scales of the
ARCI and decreases in scores on the BG scale (Drug × Time:
p < .001, bottom) relative to SAL. HM produced
statistically significant increases in PCAG scores and decreases in BG
scores at the two largest doses, whereas the other drugs produced
significant increases only after administration of the largest dose. In
addition, the PCAG score after the largest dose of HM was statistically
significantly higher than the score after the largest dose of MOR (top,
asterisk). A statistically significant effect of Drug was also found
for the AMP scale [F(3,45) = 3.3, p < .05]; however, the only significant difference
revealed by Tukey post hoc testing was between the means for HM and
MEP, neither of which was statistically different from SAL. No
statistically significant effects were observed for scores on the MBG
scale of the ARCI.
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OAC.
Statistically significant Drug × Time interactions
were found for seven of the twelve adjectives on the OAC:
"flushing" (p < .001), "skin itchy"
(p < .001), "turning of stomach"
(p < .001), "numb" (p < .001),
"dry mouth" (p < .001), "drive (motivated)" (p < .005), and "nodding" (p < .001). Ratings of "drive" decreased and ratings of the other
adjectives increased in a dose-related manner after administration of
all opioids. These effects were similar for all active drug conditions,
except for ratings of "skin itchy" and "dry mouth". Figure
2 shows that HM had the largest effect
and MEP had the least effect on ratings of "skin itchy" (left).
HM-induced increases at the 235-min time point were statistically higher than ratings after both MEP and MOR administration, and ratings
at several other time points (210, 270, 300, and 330 min) were
statistically higher than ratings after MEP. Figure 2 also shows that
MEP had the largest effect on ratings of "dry mouth" (right)
relative to HM and MOR, which produced similar, smaller increases in
ratings. A statistically significant effect of Drug was found for
ratings of "sweating" (p < .05). HM and MEP
increased ratings of "sweating", and MOR had no effect.
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VAS.
Statistically significant Drug × Time interactions
were observed for 16 of the 23 adjectives on the VAS: "stimulated
(energetic)" (p < .01), "high (`drug' high)"
(p < .001), "floating" (p < .001), "sedated (calm, tranquil)" (p < .005),
"lightheaded" (p < .001), "tingling"
(p < .01), "confused" (p < .05),
"drunk" (p < .005), "nauseous"
(p < .001), "dizzy" (p < .001),
"coasting (`spaced out')" (p < .001), "feel
good" (p < .05), "heavy or sluggish feeling" (p < .001), "difficulty concentrating"
(p < .001), "hungry" (p < .001),
and "sleepy (drowsy, tired)" (p < .001). Average
ratings for these adjectives increased after administration of active drugs except ratings of "feel good", "stimulated", and
"hungry", which decreased relative to ratings after SAL
administration. Figure 3 shows average
ratings of "dizzy" (top left) and "high" (top right). MEP
produced the largest increases in ratings of these adjectives, and
these effects tended to dissipate almost to BL levels within 15 to 55 min after each injection. A similar pattern was observed for ratings of
"floating", "lightheaded", "confused", "drunk",
"nauseous", "coasting", and "difficulty concentrating". In
general, for these latter adjectives, including "dizzy" and "high", MOR tended to produce smaller increases, or increases at
fewer time points, than did HM or MEP.
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DEL Questionnaire. The three opioids increased ratings of intensity of the drug effect in a dose-related manner (Drug × Time: p < .001). MOR-induced increases were slightly (but statistically significantly) smaller at some time points than HM- and MEP-induced increases (at 125 min compared with HM, and at 125, 135, and 185 min compared with MEP). Table 2 shows that the peak rating of intensity of the drug effect was higher after HM and MEP than after MOR. MEP's effects on this measure dissipated more quickly during the recovery period than did the effects of HM and MOR.
No statistically significant Drug × Time interactions were observed for the measure of drug liking; however, when peak and trough ratings of drug liking were analyzed by repeated-measures ANOVA (Table 2), a statistically significant effect of Drug was observed. Tukey post hoc tests revealed that mean peak and trough ratings for all opioids were significantly different from SAL but not from each other. Inspection of data for individual subjects revealed some intersubject variability in that three subjects reported consistent disliking of all three opioids, and the other 13 subjects reported both liking and disliking of opioid effects. It is interesting to note that no subjects reported consistent liking of the three opioids tested. Of the 13 subjects who reported both liking (ratings higher than 60 mm on the VAS) and disliking (ratings lower than 40 mm on the VAS) of opioid effects, there was considerable variability in the within-session pattern of liking ratings and in the number of time points within a session in which opioid effects were reported as being liked versus disliked. No obvious differences in extent of drug liking/disliking for different opioids were observed, either in the peak/trough analysis or in visual inspection of individual graphs.Postsession Adjective Checklist. Statistically significant Drug effects were found for ratings of 4 of the 17 adjectives on the postsession adjective checklist: "feel bad" (p < .05), "heavy or sluggish feeling" (p < .05), "nausea" (p < .01), and "skin itchy" (p < .05). MOR produced the only statistically significant increases relative to SAL on these four adjectives. Results for three other adjectives approached statistical significance (p < .10): "difficulty concentrating", "lightheaded", and "vomiting". For these adjectives, also, MOR produced the largest increases. Four people reported vomiting after the session in which MOR was administered. One of these subjects vomited after the HM session, and another vomited after the MEP session. In general, then, MOR appeared to produce longer-lasting unpleasant effects than HM or MEP.
Psychomotor/Cognitive Performance
Statistically significant Drug × Time interactions were
observed for Maddox-Wing (p < .001), eye-hand
coordination (p < .001), and DSST (p < .001) performance. Dose-related exophoria was observed for HM and
MOR; MEP did not induce exophoria. All opioids produced dose-related
increases in the number of mistakes on the eye-hand coordination test
at the largest dose. MOR produced the smallest increases, and HM
impaired coordination to the greatest extent in that it also impaired
performance at the second largest dose. Figure
4 shows the average number of symbols
drawn correctly on the DSST. Dose-related decreases were observed for
all drugs, with MOR producing the smallest decreases. MEP impaired DSST
performance to the largest extent 5 min after the last two injections;
this impairment was attenuated more quickly than the effects of MOR and
HM, which continued up to 210 min after the last injection (i.e., at
the 390-min time point). Results for the auditory reaction test
approached statistical significance (p < .10), with
MOR producing smaller increases in reaction time than the other
opioids. No statistically significant differences occurred for results
of the logical reasoning test.
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Mean peak impairment is shown in Table 2 for psychomotor measures that showed statistically significant effects of Drug on mean peak or trough scores. These data are similar to the results described above. That is, HM produced the highest peak exophoria score, and the peak after MEP administration was not statistically different from SAL. The maximum number of mistakes on the eye-hand coordination test induced by MOR was not significantly different from SAL, but the peaks for HM and MEP were. Although the trough values for number of symbols drawn correctly on the DSST were lower for HM and MEP, these values were not significantly different from MOR.
Physiological Measures
Figure 5 shows that pupil diameter
decreased as a function of dose administered (Drug × Time:
p < .001) and that MOR and HM produced more miosis
than MEP. A statistically significant Drug × Time interaction was
also observed for pulse (p < .05) and respiration rate
(p < .05). However, only one time point for pulse and
four time points for respiration rate showed statistically significant differences relative to SAL, and only one of these differences was
clinically significant (at least 20% difference from SAL): the
respiration rate at the 330-min time point during the MOR condition was
20.2% lower than the rate at the 330-min time point during the SAL
condition.
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Trough effects for respiration rate and miosis are shown in Table 2. MEP produced the least miosis by this measure, also; mean trough effects of HM and MOR, which were similar, were statistically lower than the mean value for MEP. HM and MOR produced similar mean trough respiration rates, and the trough respiration rate for MEP was not statistically different from SAL.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Orderly dose-response functions were observed for subjective,
psychomotor, and miotic effects; therefore, our cumulative-dosing procedure appears to be an effective way to determine dose-response functions for opioids in healthy volunteers within a single session. In
general, MOR tended to produce the mildest effects on mood and
psychomotor performance relative to HM and MEP. These results replicate
those found in previous single-dosing studies conducted in our
laboratory, in that mood effects noted with MEP (Zacny et al., 1993)
were more intense than those observed in other studies with MOR (Zacny
et al., 1994a, b; 1997a, b; 1998). Psychomotor impairment in these
previous studies was modest at best, with MOR and MEP producing either
no or slight impairment. In the present study psychomotor performance
was more impaired than in these other studies, a result that is not
unexpected, given that although we tested identical doses in the
present study, we administered them an hour apart (rather than in
separate sessions) such that, because effects of the previous dose had
not completely worn off before the next dose was injected, the largest
doses tested in the present study (the cumulative doses) were probably
larger than the largest doses tested in the single-dosing studies. It is not surprising, therefore, that milder effects were observed in the
single-dosing studies compared with the present one. In the only
studies that have examined HM effects in healthy volunteers, almost no
effects on mood and psychomotor performance were observed, and those
that were reported were mild (Oliveto et al., 1994; Pickworth et al.,
1997). These studies tested 1 to 6 mg oral HM; however, 7.5 mg is the
oral dose thought to be equianalgesic to the largest dose injected in
the present study (1.3 mg/70 kg i.v. [cumulative dose = 2.28 mg/70 kg]; Jaffe and Martin, 1990). Therefore, the milder effects
observed in those studies compared with the present one may be due to
the smaller doses tested and/or the route of administration.
Some differences were observed in the patterns of subjective effects of
different opioids. MEP appeared to be the most "intoxicating" of
the opioids, in that it produced the largest mean peak ratings of
"high", "floating", "confused", "drunk",
"coasting", and "difficulty concentrating". These more intense
effects were short-lived, however; they peaked 5 min after drug
injection and recovered, sometimes to BL levels, within 55 min. A
number of effects of HM and MOR peaked 15 to 55 min after an injection,
and recovery was slower than with MEP. Given that the onset of
analgesia is slightly faster and the duration of analgesia is slightly
shorter for MEP than for HM and MOR (Jaffe and Martin, 1990; Medical
Economics Data Production, 1996), these differences in time course of
subjective effects are not entirely unexpected. The present data point
to the importance of assessing dependent measures at multiple time points shortly after drug administration, as well as assessing them for
a prolonged period of time (i.e., recovery). Omission of the
dependent-measures assessment 5 min after each injection would have
made MEP's peak effects appear smaller. Testing during the recovery
period revealed that HM and MOR continued to produce "unpleasant"
subjective effects (increased ratings of "unpleasant bodily
sensations", "feel bad", and "nauseous") for 4 h after the last injection. Our postsession questionnaire also revealed that
MOR continued to have "unpleasant" effects (increased ratings of
"feel bad", "heavy or sluggish", "nausea", "skin
itchy", "vomiting") even after subjects left the laboratory, and
Seevers and Pfeiffer (1936) also found more prolonged side effects of
MOR compared with HM in normal volunteers (see also Lasagna et al.,
1955). Although MOR appeared to produce the mildest subjective and
psychomotor effects during the 4-h drug-administration/testing period,
it continued to have "negative" effects, which occurred into the recovery (as did HM's) and postsession periods.
MEP had the mildest effect on ratings of "skin itchy" and on miosis
and the greatest effect on ratings of "dry mouth". Woodhouse et al.
(1996) also found that patients given MEP reported being less itchy
than patients given MOR, and Rapp et al. (1996) found that patients
receiving MOR or HM reported similar levels of itchiness. In the
present study, HM appeared to increase self-reported itchiness to a
greater extent than MOR; however, the difference in means for MOR and
HM was statistically significant at only one time point (Fig. 2, left),
and the peak ratings were not significantly different (Table 2). In a
study with former opiate abusers (Jasinski and Preston, 1986) and in
the single-dosing study by Zacny et al. (1993), MEP was less potent in
inducing miosis than it was in inducing MOR-like subjective effects
(see also Jasinski and Nutt, 1973), a result that is consistent with
results of the present study. That is, the same doses of MEP that
produced more intense subjective effects than equianalgesic doses of
MOR also produced less miosis. MEP is known to have anticholinergic
properties (Batterman, 1943; Wynn et al., 1990), and these properties
may account for MEP's lesser effect on pupil diameter (Mansky, 1978;
Clark et al., 1995) and its greater effect on ratings of "dry
mouth" (Parrott, 1986; Sannita et al., 1987; Zacny et al., 1993).
Inter- and intrasubject variability in extent of drug liking was
observed in the present study and has been reported in previous opioid
studies with healthy volunteers who have no history of opioid
dependence (Lasagna et al., 1955; Zacny et al., 1992, 1993, 1994a). In
contrast with subjects with a history of opioid dependence, who
consistently report "pleasant" effects of µ-agonist opioids (Jasinski and Nutt, 1973; Jasinski et al., 1977; Jasinski and Preston,
1986; Preston and Bigelow, 1993, 1994; Strain et al., 1993), subjects
in the population we sample do not consistently report pleasant
effects, and indeed may report unpleasant effects or a disliking of the
drugs. Zacny et al. (1994a) found that about half the subjects tested
with MOR 2.5, 5, and 10 mg/70 kg reported liking effects of 5 and 10 mg/70 kg at one or more time points, and four of these six subjects
first liked then disliked the effects (i.e., biphasic response). In the
study with MEP 17.5, 35, and 70 mg/70 kg, about half the subjects liked
the two large doses of MEP within 45 min of the injection; however,
half reported neutrality toward or disliking of the drug effects at
these time points (Zacny et al., 1993). Seevers and Pfeiffer (1936)
reported that although one of their subjects became euphoric after drug administration, none of the subjects (N = 8) expressed
a "desire for repetition" of the procedures, which included i.m.
and s.c. MOR 8 mg and HM 1 mg. Similarly, s.c. MOR 8 and 15 mg and
heroin 2 and 4 mg produced more reports of "unpleasant" than
"pleasant" effects, and reports of "unpleasant" effects
increased with increasing dose (Lasagna et al., 1955). In the present
study, although 10, 12, and 11 subjects reported liking MOR, HM, and
MEP, respectively, at one or more time points, 12, 14, and 13 subjects,
respectively, also expressed a disliking of these drugs at one or more
time points. These opioids, then, were at least as likely to produce disliking as liking. In addition, other dependent measures that are
putatively associated with abuse liability (MBG scores on the ARCI,
ratings of "carefree", "good mood", "elated") showed no
statistically significant Drug or Drug × Time effects, and ratings of "feel good" decreased after drug administration relative to SAL. The present results are in agreement with the studies described
above and suggest that although opioid µ agonists can induce drug
liking in healthy volunteers, they do not consistently increase ratings
of drug liking or other effects thought to be associated with abuse
potential in people with no history of drug abuse. Data from this
population are important to collect because it is this population that
makes up the majority of people who will be prescribed these drugs for
pain relief.
In most cases, results of both time course and peak/trough analyses were concordant; for example, based on the time course data, MEP appeared to produce the largest maximum increases in VAS ratings of "dizzy" and "high" (Fig. 3, top), and peak effects were also statistically higher for MEP than for HM or MOR (Table 2). MEP appeared to have the least effect on pupil diameter when either time course (Fig. 5) or trough (Table 2) effects were analyzed. Several other dependent measures showed a concordance in results of the two types of analyses (e.g., ARCI scores, ratings of several OAC and VAS adjectives, exophoria, eye-hand coordination, DSST performance). In other cases, results of the two analyses were discordant. For example, MOR appeared to have the least effect on several subjective-effects measures when Drug × Time effects were analyzed, but in many cases, no statistically significant differences in peak or trough effects were observed among active-drug conditions (e.g., VAS ratings of "floating", "lightheaded"). No statistically significant differences in peak effects of the opioids were revealed by Tukey post hoc testing for ratings of "nauseous" (Table 2), even though examination of the means of all time points suggests that MEP produced the largest maximum effect (Fig. 3, bottom left). This type of result suggests that the drugs did not differ so much in their maximum effect on ratings of "nausea" (and several other dependent measures) as might be suggested by the Drug × Time analysis and that inclusion of both types of analysis results in a more complete characterization of opioid effects.
In summary, our cumulative-dosing procedure appears to be an effective
methodology for determining dose-response functions for an opioid
within a single session. Some studies that have compared the results of
cumulative and noncumulative dosing have found similar dose-response
curves (Wenger, 1980; McMillan et al., 1982), but others have found
differences in results of the two procedures (Winger et al., 1989;
Clark et al., 1990; Gauvin et al., 1997), including apparent
within-session sensitization or tolerance during cumulative dosing
(Thompson et al., 1983). We do not know whether sensitization or
tolerance occurred in the present study because we did not compare
directly the effects of cumulative versus noncumulative dosing.
However, we found no apparent indication of either, given the orderly,
dose-related effects that were observed and the fact that these effects
were at least as strong as those observed in the single-dosing studies with MEP and MOR (Zacny et al., 1993, 1994a). The present procedure seems ideal for characterizing effects of multiple opioids within the
same study in which different doses of each drug are to be tested.
Inclusion of multiple doses of each drug to be compared is imperative
because relying on effects of only one dose results in an incomplete
characterization and limits the generality of results.
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Acknowledgments |
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The authors wish to thank Dennis Coalson, M.D., Jerome Klafta, M.D, P. Allan Klock, M.D., Parvine Sadeghi, M.D., Robert Shaughnessy, Mary Maurer, and Nada Williamson for administering the agents and monitoring the physiological status of the subjects; Karin Kirulis for screening potential subjects and conducting the structured interviews; Joanna Hill for conducting experimental sessions and compiling the data; and Linda Felch for helpful comments on statistical analyses.
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Footnotes |
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Accepted for publication February 13, 1999.
Received for publication September 3, 1998.
1 This research was supported by National Institute on Drug Abuse Grant DA-08573. Portions of these data were presented at the 60th Annual Scientific Meeting of the College on Problems of Drug Dependence, Scottsdale, Arizona; at the 11th Annual Scientific Meeting of the Great Lakes Chapter-American Society for Pharmacology and Experimental Therapeutics, Chicago, Illinois; and at the 72nd Clinical and Scientific Congress of the International Anesthesia Research Society, Orlando, Florida.
Send reprint requests to: Dr. Diana J. Walker, Ph.D., Dept. of Anesthesia and Critical Care, The University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637. E-mail: dwalker{at}airway.uchicago.edu
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Abbreviations |
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ARCI, Addiction Research Center Inventory; PCAG, pentobarbital-chlorpromazine-alcohol group; BG, benzedrine group; AMP, amphetamine; LSD, lysergic acid diethylamide; MBG, morphine-benzedrine group; VAS, visual analog scale; DEL, Drug Effect/Liking; OAC, Opiate Adjective Checklist; DSST, Digit Symbol Substitution Test; HM, hydromorphone; MEP, meperidine; MOR, morphine; SAL, saline; BL, baseline.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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indicates that the difference in means for HM and MEP was
statistically significant at that time point. Ratings could vary from 0 ("not at all") to 4 ("extremely"). BL indicates the period
immediately before the first injection. Arrows indicate that injections
occurred at 0, 60, 120, and 180 min. Drug doses (absolute amount per
injection) were HM 0, 0.33, 0.65, and 1.3 mg/70 kg; MEP 0, 17.5, 35, and 70 mg/70 kg; and MOR 0, 2.5, 5, and 10 mg/70 kg.
