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Vol. 280, Issue 3, 1159-1169, 1997
Department of Anesthesia and Critical Care, The Pritzker School of Medicine, The University of Chicago, Chicago, Illinois
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Abstract |
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 Top
Abstract
Introduction
Methods
Results
Discussion
References
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The purposes of this study were to characterize the subjective, psychomotor and physiological effects of nalbuphine in healthy non-drug abusing volunteers and to compare and contrast the effects of equianalgesic doses of nalbuphine and morphine. Subjects (12 males, 4 females) without histories of opiate dependence were injected in an upper extremity vein with 0, 2.5, 5.0 or 10 mg/70 kg nalbuphine, or with 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. The 10-mg doses of nalbuphine and morphine are considered equianalgesic and are doses commonly given for relief of postoperative pain. Subjective effects of nalbuphine included increased scores on the Pentobarbital-Chlorpromazine-Alcohol Group scale and the Lysergic Acid Diethylamide scale of the Addiction Research Center Inventory; increased adjective checklist ratings of "nodding," "numb" and "sweating"; increased visual analog scale ratings of "coasting or spaced out," "high" and "sleepy" and increased "feel drug effect" and drug-liking ratings. Ten milligrams of nalbuphine had subjective effects similar, and similar in magnitude, to those of 10 mg of morphine. Nalbuphine produced exophoria and impairment on the Digit Symbol Substitution Test in a dose-related fashion. Ten milligrams of morphine produced exophoria but did not affect performance on the Digit Symbol Substitution Test. Both nalbuphine and morphine induced miosis and decreases in respiration rate. The results of the present study demonstrate that 2.5 to 10 mg nalbuphine had orderly, dose-related effects on subjective, psychomotor and physiological variables. The results also indicate that 10 mg of nalbuphine produces a profile of subjective, psychomotor and physiological effects similar to that of an equianalgesic dose of morphine (10 mg). The similarity in profiles between drugs at this dose is consistent with both infrahuman studies, which suggests that nalbuphine is a mu agonist, and studies with nondependent opioid abusers, in which relatively low doses of nalbuphine (such as 10 mg) produce morphine-like effects.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Nalbuphine is an opioid analgesic
that is indicated for mild to moderate pain. It is not recommended for
severe pain because of its putative low analgesic efficacy (Walker
et al., 1993
; Gerak et al., 1994) and a ceiling
effect on analgesia (Gal et al., 1982). What makes it
attractive in some instances for pain control is that a ceiling effect
is also found with respiratory depression (Romagnoli and Keats, 1980;
Gal et al., 1982). Such a ceiling effect for analgesia and
respiratory depression is not found with the high-efficacy
mu agonist morphine. Nalbuphine is traditionally considered
to fall under the class of opioids known as mixed agonist-antagonists (Jaffe and Martin, 1990). It has affinity at both mu and
kappa receptors (De Souza et al., 1988; Clark
et al., 1989) and is thought to have efficacy as well at
both of these receptors (e.g., Pick et al., 1992;
Walker et al., 1993). One recent study in mice provided convincing evidence that the analgesic effects of nalbuphine were mediated by the kappa receptor (Pick et al.,
1992), although another study in rats provided equally convincing
evidence that the analgesic effects were mediated at the mu
receptor (Walker et al., 1993).
A number of infrahuman studies have been used to characterize the
behavioral effects of nalbuphine, especially those effects that are
related to abuse liability. First, animals will self-administer nalbuphine at a rate greater than saline, which indicates that it can
function as a reinforcer (Steinfels et al., 1982; Young et al., 1984). In addition, nalbuphine lowers the threshold
for brain-stimulation reward, in the same manner as drugs of abuse such
as morphine and cocaine (Unterwald and Kornetsky, 1986), a further
piece of evidence that the drug has reinforcing effects. Second, in
drug discrimination studies, mu agonists such as fentanyl, etorphine, morphine and methadone substitute for the nalbuphine discriminative stimulus (Walker and Young, 1993; Gerak and France, 1995), and nalbuphine, in turn, substitutes for etorphine, fentanyl and
morphine (e.g., Shannon and Holtzman, 1976; Walker et
al., 1994; Young et al., 1984, 1991; Vanacek and Young,
1995). In contrast, kappa agonists and nalbuphine do not
consistently substitute for each other (Picker and Dykstra, 1989;
Walker and Young, 1993; Young et al., 1984; Gerak and
France, 1995). These data indicate that the interoceptive effects of
nalbuphine are mediated at the mu receptor.
In human laboratory studies examining nalbuphine, behavioral
assessments have focused on the subjective effects, the discriminative stimulus effects and the psychomotor-impairing effects of the drug.
Elliott et al. (1970) studied the subjective and miotic effects of 10 mg of nalbuphine and morphine (i.m.) in postaddicts in a
double-blind, two-group, 6-day (i.e., subchronic) study. The
doses of nalbuphine and morphine tested were equianalgesic. Subjective
effects were measured by a variant of the SDQ (Fraser et
al., 1961; Martin, 1967). The SDQ comprises scales that assess self-reports of strength of drug effect, identification of the drug
from a list of possible drugs, drug symptomatology and drug liking. The
SDQ indicated that the subjective effects of nalbuphine and morphine
were similar, and subjects in both drug groups reported liking the
drug. Degree of miosis was also similar between the two drugs. Jasinski
and Manski (1972) compared the subjective effects of 8, 24 and 72 mg of
nalbuphine (s.c.) to those of 10 and 20 mg of morphine (all doses
administered per 70 kg b.wt.) in non-physically dependent prisoners
with histories of opioid abuse. The lowest dose of nalbuphine tended to
have subjective effects in common with the lower dose of morphine.
However, higher doses of nalbuphine increased ratings of "sleepy"
and "drunk" on the SDQ, as well as increasing scores on the PCAG
and LSD scales of the ARCI, effects that were not noted with either
dose of morphine. The authors suggested that the qualitative profile of
subjective effects of nalbuphine may be contingent on the doses tested.
In a study with non-drug abusers, volunteers given 10.5 mg of
nalbuphine per 70 kg b.wt. (i.m.) reported increased VAS ratings of
"drowsiness," "clumsiness," "muzziness," and "relaxed"
for up to 2.5 h after drug administration (Saarialho-Kere, 1988).
In two other studies that focused on the respiratory depressant effects
of nalbuphine (as compared with morphine), subjective drug effects of
single doses of nalbuphine (i.v.) of 10 mg/70 kg and multiple dosing up
to 60 mg/70 kg were elicited by open-ended questions (Romagnoli and
Keats, 1980; Gal et al., 1982). Drowsiness and sedation were the most prominent subjective effects in both the acute and the multiple-dosing regimen.
A number of studies with nondependent opioid-abusing volunteers
examined the substitutability of i.m. nalbuphine for the discriminative stimulus effects of i.m. hydromorphone, pentazocine and butorphanol. Nalbuphine substituted for hydromorphone in a two-way discrimination (training drugs: hydromorphone, saline) (Preston et al.,
1992) but engendered both hydromorphone- and pentazocine-appropriate responding in a three-way discrimination (training drugs:
hydromorphone, pentazocine, saline) (Preston et al., 1989b).
In both studies, the subjective effects of nalbuphine differed from
those of hydromorphone in that hydromorphone, but not nalbuphine,
increased ARCI MBG scores and Agonist subscale scores from an opioid
adjective rating scale. In the most recent study in this series,
nalbuphine engendered both hydromorphone- and butorphanol-appropriate
responding in a three-way discrimination (training drugs:
hydromorphone, butorphanol, saline), up to doses of 12 mg/70 kg
(Preston and Bigelow, 1994). At a higher dose, 24 mg/70 kg, nalbuphine
engendered primarily butorphanol-appropriate responding, its subjective
effects resembling those of butorphanol more than those of
hydromorphone. The authors concluded in this study that nalbuphine is
more kappa-like than mu-like. Nalbuphine has been
tested in opioid-dependent volunteers who have been trained to
discriminate among hydromorphone, naloxone and saline. In these
volunteers, nalbuphine had no agonist effects and substituted for the
naloxone discriminative stimulus (Preston et al., 1990).
This latter finding is consistent with the finding that nalbuphine,
like other mixed agonist-antagonists, can precipitate withdrawal in
methadone-maintained patients (Preston et al., 1989a).
Nalbuphine in several studies has not impaired psychomotor performance,
as measured by the DSST, in either dependent or nondependent opioid
users (Preston et al., 1989a,b, 1990, 1992; Preston and Bigelow, 1994). In contrast, in a study using non-drug abusing volunteers, DSST performance and several other indices of psychomotor performance were impaired by nalbuphine at a dose of 10.5 mg/70 kg
(Saarialho-Kere, 1988). Thus there may be differences in the degree to
which this drug impairs performance, contingent on the drug history of
the individual being tested.
The effects of nalbuphine, especially as they are related to abuse
liability, have been well characterized in opioid abusers. This is less
true for non-drug abusers; no study to date has constructed a
dose-response function of nalbuphine using a methodology that is well
accepted in abuse liability testing. We have recently conducted a
number of studies with other opioids, including fentanyl, meperidine,
morphine, dezocine and butorphanol, to better characterize opioid
effects, as the effects are related to abuse liability, in non-drug
abusing volunteers (Zacny et al., 1992a,b, 1993, 1994a,b, 1996). The present study examined, in non-drug abusing volunteers, the
subjective, psychomotor and physiological effects of a range of doses
of nalbuphine. In addition, the highest dose of nalbuphine tested was
compared with an equianalgesic dose of morphine to determine the extent
to which single equianalgesic doses of the two opioids differ from, or
are similar to, each other.
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Methods |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Subjects
Candidates were recruited via posters and local
newspaper advertisements. Potential subjects who consumed, on average,
one alcoholic drink per week and were between the ages of 21 and 39 were scheduled for a screening interview with one of our research personnel. During the interview, candidates completed the SCL-90, a
questionnaire designed to assess psychiatric symptomatology (Derogatis,
et al., 1973) and a health questionnaire designed to
determine their psychiatric and mental status. Candidates with any
psychiatric problems, including drug-related problems, alcohol-related problems and Diagnostic and Statistical Manual of Mental
Disorders-III-Revised Axis I psychiatric disorders (American
Psychiatric Association, 1987), were excluded on the basis of a
structured psychiatric interview.
Potential subjects participated in an orientation session before the start of the study. Before the orientation session, subjects signed a written consent form that described the study in detail. In the consent form, subjects were told that the i.v. drugs to be used in the study were drugs commonly used in medical settings and might come from one of six classes: sedative, stimulant, opiate, general anesthetic (at subanesthetic doses), alcohol or placebo. Subjects then received a resting-state electrocardiogram, and a physician took a medical history and performed an examination. Any participants who had experienced any adverse reactions to general anesthetics and any who had pulmonary, renal, hepatic or cardiac problems were excluded from the study. Subjects were required to give a urine sample, on which we performed the Enzymatic Multiplied Immunoassay Technique (EMIT) toxicology screening for acetaminophen, alcohol, amphetamines, barbituates, benzodiazepines, cocaine metabolites, opiates, phencyclidine and salicylate. None of the subjects tested positive for any of these drugs or metabolites. Mood and psychomotor tests were practiced by volunteers during the orientation in order to acclimate them to the tests and also to avoid any practice effects on psychomotor testing during experimental sessions. Payment for the study was made at the debriefing, which was held after the study was completed. The study was approved by the local Institutional Review Board.
Sixteen healthy volunteers, 12 male and four female (age range: 21-37 years; mean age: 27.7 years), participated. All volunteers had some prior use of recreational drugs, but none had histories indicative of dependence. Their self-reported number of alcohol drinks consumed per week (over the last 30 days) was 3.9 (range: 0.5-12). One volunteer reported smoking marijuana on a weekly basis (0.5 joint/week). Regarding lifetime drug use, two volunteers reported prior use of stimulants (including cocaine), five volunteers reported prior use of hallucinogens (LSD, mushrooms) and 12 volunteers reported prior use of cannabinoids. Eight of the 16 subjects had no prior exposure to opiates. The other eight had been prescribed opiates (reported by subjects as codeine, as acetaminophen with codeine or as "painkillers") in the past for pain relief. No subjects reported using opiates recreationally in their lifetime.
Procedure
Experimental design.
A randomized, placebo-controlled,
double-blind, crossover trial was conducted. Subjects were injected in
an upper extremity vein with saline, with 2.5, 5.0 or 10 mg/70 kg
nalbuphine or with 10 mg/70 kg morphine, over a 15-s interval. We chose
the 10-mg dose of morphine because it is considered equianalgesic to
the 10-mg dose of nalbuphine (Jaffe and Martin, 1990). Subjects
participated in five sessions spaced at least one week apart. Sessions
were approximately 360 min in duration.
Experimental sessions. The experiment took place in a departmental laboratory. Subjects were instructed not to eat food or drink any nonclear liquids for 4 h, not to drink clear liquids for 2 h and not to use any drugs (including alcohol but excluding normal amounts of caffeine and nicotine) 24 h before sessions. A toxicology screening was required before the start of each session for all participants, as was a pregnancy test for all female participants. Subjects were also given a breath alcohol test so we could be sure they had no alcohol in their system. Subjects next completed several subjective-effects forms and psychomotor tests, and their respiratory rate, HR, noninvasive arterial oxygen saturation and blood pressure were monitored. Subjects then reclined in a semirecumbent position on a bed, and, using proper sterile technique, an anesthesiologist injected into one of the subject's upper-extremity veins either morphine, nalbuphine or saline over 15 s. Before the injection the subject was told, "The injection you are about to receive may or may not contain a drug." The drug had previously been drawn up by one anesthesiologist and was administered by another in order to preserve the double-blind nature of the study. However, the injecting anesthesiologist was aware of the drugs involved, so that if an adverse event occurred, appropriate measures could be taken to ensure the safety and well-being of the subject. The anesthesiologist remained in the immediate area for 15 min after the injection to monitor the subject's vital signs. At periodic intervals after the injection (see below), the mood, psychomotor performance and physiological status of the subject were assessed. Drinking water was permitted 90 min after the injection, but eating was not allowed during the session. A snack was served to the subject after the session was terminated. When no tests were scheduled, subjects were free to engage in sedentary recreational activities such as reading, listening to the radio or to cassette tapes 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. After completion of sessions, subjects were transported home via a livery service with instructions not to engage in certain activities (e.g., cooking with a stove, driving an automobile, caring for children, drinking alcohol) for the next 12 h.
Dependent Measures
Session measures. The following tests were completed before injection and 15, 60, 120, 180, 240 and 300 min after injection. On all of these measures, subjects did not have access to how they responded on previous tests from the same session. When subjects performed computerized tests, they had to move from the middle of the bed to the edge of the bed, still in a semirecumbent position. When subjects performed paper-and-pencil tests, they did not have to move at all. Thus subject movement during and before testing was minimal in the present study. Table 1 lists the order of testing, which remained invariant across subjects and sessions.
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Subjective measures.
1. The ARCI is a true-false
questionnaire designed to differentiate among different classes of
psychoactive drugs (Haertzen, 1966). We used a computerized short form
of the ARCI (Martin et al., 1971), which had 49 items and
yielded scores for five different scales: PCAG, sensitive to sedative
effects; BG and AMP, sensitive to amphetamine-like effects; LSD,
sensitive to somatic and dysphoric changes; and MBG, often described as
euphoria.
)] and a list reported as sensitive to the
somatic and subjective effects of opiates from the mu and mixed agonist-antagonist class (Preston et al., 1989b;
Strain et al., 1993). The checklist consisted of 14 items
that the subject rated on a 5-point scale from 0 ("not at all") to
4 ("extremely"). The items were as follows: "carefree,"
"depressed," "drive (motivated)," "dry mouth,"
"floating," "flushing," "good mood," "headache," "nodding," "numb," "skin itchy," "sleepy,"
"sweating" and "turning of stomach."
3. A locally developed VAS consisted of twenty-three 100-mm lines
labelled with the following phrases: "coasting (spaced out)," "confused," "difficulty concentrating," "dizzy,"
"down," "drunk," "elated (very happy)," "feel bad,"
"feel good," "floating," "having pleasant bodily
sensations," "having pleasant thoughts," "having unpleasant
bodily sensations," "having unpleasant thoughts," "heavy or
sluggish feeling," "high," "hungry," "lightheaded,"
"nauseous," "sedated (calm, tranquil)," "sleepy (drowsy,
tired)," "stimulated (energetic)" and "tingling." Subjects on
this paper-and-pencil test were instructed to place a mark on each line
indicating how they felt at the moment, ranging from "not at all"
to "extremely." In addition to the time-points listed above, the
VAS was completed at 5, 30, 45, 75, 90, 105, 150 and 210 min after
injection.
4. The Drug Effects/Liking questionnaire assessed the extent to which
subjects currently felt a drug effect, 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 feel an effect, but it
is not real strong"; 4 = "I feel a strong effect"; 5 = "I feel a very strong effect"). It also assessed the extent to which subjects currently liked the drug effect on a 100-mm line (0 = dislike a lot; 50 = neutral; 100 = like a lot). In addition to the time-points listed above, the Drug Effects/Liking Questionnaire was completed at 5, 30, 45, 75, 90, 105, 150 and 210 min after injection.
5. Subjects were given an adjective rating checklist to take home with
them and were asked to complete it 24 h later and to note whether
they had any of the symptoms listed on the checklist ("anxious,"
"coasting (spaced out)," "clumsy," "confused,"
"difficulty concentrating," "down," "dry mouth,"
"excessive hunger," "excessive thirst," "feel bad," "feel
good," "headache," "heavy or sluggish feeling,"
"lightheaded," "nausea," "skin itchy" and "vomiting") during the 24 h after the session. Each symptom on this
postsession questionnaire was rated on a 5-point scale ranging from
"not at all" (0) to "extremely" (4).
Subjects were also given, to fill out 24 h after each session, a
multiple-choice drug preference questionnaire based on that developed
by Griffiths and his associates (1993). On the form, subjects were
given 40 drug vs. money options and, for each option, were
asked to choose either the money or the preceding drug condition. The
money option increased in amount across options from $0.10 in option 1 to $30.10 in option 40. The instructions were as follows: "If, at the
end of this study, you participated in a session in which you could
choose between being injected with a drug you were injected with
yesterday or being injected with saline (placebo) and receiving a
certain amount of money, what would you choose? For each number (40),
check whether you prefer the drug or the money + saline (placebo)
condition. YOU WILL NOT BE ASKED TO PARTICIPATE IN SUCH A SESSION; WE
ARE ASKING A HYPOTHETICAL QUESTION, BUT PLEASE TRY TO ANSWER AS IF YOU
WERE GOING TO PARTICIPATE IN THIS EXTRA SESSION." The option at which
the subject chose money over drug was called the "crossover point."
It has been established in recreational drug users that a higher dose
of a drug (pentobarbital) has a greater crossover point (subjects are
willing to forgo more money for the drug) than a lower dose (Griffiths
et al., 1993), in much the same way that "crossover
points" or "breakpoints" are greater for higher doses of drugs in
a progressive ratio schedule of reinforcement. This methodology was
used as another means of assessing liking of drug effects, on the
assumption that drugs that were liked more would have a higher
crossover point than drugs that were disliked. The preference form was
not a measure of the reinforcing effects of nalbuphine or
morphine, because no choices made on the forms were actually
administered to the subject, and the subject was aware that the
questions asked on the form were hypothetical in nature.
Psychomotor/cognitive performance.
The following six tests
were chosen because we have employed these tests in our prior opioid
studies and because previous studies from other laboratories have
indicated that the specific parameters of psychomotor/cognitive
performance that the tests are designed to measure can be affected by
opioids (cf., Zacny 1995).
).
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 was
to keep a small cross, which was controlled by the mouse, inside the
moving target circle at all times as the circle moved randomly around
the screen. The length of the test was 1 min. The dependent measure was
number of mistakes (i.e., number of times the cross exceeded
one centimeter from the center of the target circle).
3. The DSST was a 1-min paper-and-pencil test that required the
participant to replace digits with corresponding symbols according to a
digit-symbol code listed on the top of the paper (Wechsler, 1958). The
score was the correct number of symbols drawn by the participant. The
DSST evaluates changes in information-processing performance and the
ability to concentrate (Hindmarch, 1980).
4. An auditory reaction test measured the time it took for subjects to
react to an auditory stimulus (Nuotto and Korttila, 1991). Ten 50-dBA
computer-generated tones were delivered at random time intervals
(between 1 and 10 s) in a 1-min time period. The tone remained on
until subjects depressed the computer keyboard spacebar or until 2 s had elapsed, whichever occurred first. The mean reaction time (in
seconds) was the dependent measure.
5. A logical reasoning test measured higher mental processes such as
reasoning, logic and verbal ability. This 1-min computerized test was
similar to the Logical Reasoning Test developed by Baddeley (1968)
except for test duration (1 min vs. 3 min) and presentation medium (computer vs. paper-and-pencil). The logical
reasoning test employed five grammatical transformations
(e.g., true vs. false statements, use of the verb
"precedes" vs. 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 key or the 0 key on the number pad, which
corresponded to true and false, respectively. The number of statements
answered correctly was the dependent measure.
6. A locally developed memory test measured short-term and long-term
memory by presenting a sequential list of 15 words on the computer.
These 15 words were presented in approximately 30 s. The subject
was then given 120 s to write down as many of the words as he or
she could remember. Different word lists were used for all sessions,
including the practice session. To ensure comparability of words across
sessions, the 15-word lists were equated on factors such as
image-evoking ability, degree of meaningfulness and frequency of
usage (Paivio et al., 1968). The words in the lists had
ratings of imagery and concreteness of greater than 5.0 and had
frequency of usage greater than 20 per million (Thorndike and Lorge,
1944). The list was presented 60 min after the injection. The subjects were asked to recall the list immediately after its presentation and at
300 min after injection.
Physiological measures. Five physiological measures were assessed: HR, blood pressure, arterial oxygen saturation, respiration rate and miosis. HR, blood pressure and arterial oxygen saturation were measured noninvasively with a Propaq 104 (Physiological Systems, Inc., Beaverton, Oregon). Respiration rate was the number of breaths that the subject took in 30 s (multiplied by 2 to get breaths per minute). This was assessed by counting the number of times the subject's chest or stomach rose and fell and was measured by one of the experimenters (KC), who was blind to the dose and drug being administered. HR, blood pressure, arterial oxygen saturation and respiratory rate were assessed at the time-points listed above. Miosis, or pupil constriction, is a physiological marker of opiate effects and was measured by photographing the subject's right pupil in a dimly lit room. Miosis was measured before injection and 15, 60, 120, 180 and 300 min after injection.
Data Analysis
Two sets of repeated-measures analysis of variance (ANOVA) were used for statistical treatment of the data. The first analysis examined nalbuphine effects: Factors were Dose (0, 2.5, 5.0 and 10 mg/70 kg b.wt.) and Time (1-15 levels). The second analysis compared peak and/or trough effects of saline, 10 mg nalbuphine and 10 mg morphine. Only postinjection values were included in this analysis. F values were considered significant for P < .05 with adjustments of within-factor degrees of freedom (Huynh-Feldt) to protect against violations of symmetry. Tukey post-hoc testing was done on the first set of ANOVAs, comparing drug responses to saline at each time-point, and on the second set of ANOVAs, comparing all of the three conditions to each other. Variance measures that are reported adjacent to ratings and scores represent S.E.M.
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Results |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Subjective Effects
ARCI. Nalbuphine.
Significant effects were obtained on
the PCAG (Dose × Time: P < .005), BG (Dose: P < .01)
and LSD (Dose: P < .005) scales. In a dose-related manner, PCAG
and LSD scores increased and BG scores decreased after nalbuphine
injection (fig. 1). Scores on the LSD scale peaked by 60 min after injection and declined thereafter, whereas scores on the PCAG
scale did not peak until 180 min after injection. Scores on the BG
scale had declined to near trough levels by 60 min after injection and
remained depressed for another 120 to 180 min. For comparison purposes,
figure 1 also shows scores from the 10 mg morphine condition. Time
course and magnitude of effects were similar between 10 mg morphine and
10 mg nalbuphine on the three ARCI scales.
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Adjective Checklist. Nalbuphine. Significant increases were obtained on five adjectives from the adjective checklist: "flushing" (Dose: P < .05), "nodding" (Dose × Time: P < .005), "numb" (Dose × Time: P < .05) "sweating" (Dose × Time: P < .05) and "turning of stomach" (Dose: P < .05). The effects of nalbuphine were dose-related; in addition, some effects ("flushing," "numb," "sweating") peaked soon after injection and declined steadily thereafter, whereas others ("nodding," "stomach turning") peaked later in the session.
Peak and trough effects. Table 3 presents mean peak and trough effects of adjective checklist ratings that were sensitive to 10 mg nalbuphine and/or 10 mg morphine. Peak drug effects, as well as time course of effects, were similar between nalbuphine and morphine on ratings of "nodding" and "numb." Ten milligrams of nalbuphine significantly increased the rating "sweating" relative to the saline condition, whereas 10 mg morphine did not differ significantly from saline. Peak ratings of "dry mouth" and "flushing" and trough ratings of "drive (motivated)" were significantly greater in the 10 mg morphine condition relative to the saline condition. Ten milligrams of nalbuphine had no significant effects on these ratings.
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VAS. Nalbuphine.
Significant Dose × Time effects
(except where otherwise noted) were obtained on ratings of "coasting
(spaced out)" (P < .001), "dizzy" (P < .05),
"floating" (P < .001), "having pleasant bodily sensations" (P < .001), "heavy or sluggish feeling" (P < .01) [fig. 2, left frame], "high" (P < .001) [fig. 2, center frame], "lightheaded" (P < .001),
"sedated" (Dose: P < .005), "sleepy (drowsy, tired)"
(P < .001) [fig. 2, right frame] and "tingling" (P < .05). All of these VAS ratings increased after drug injection and were
affected by nalbuphine in a dose-related manner. As with the ARCI,
latency to peak drug effects differed depending on what VAS adjective
was being measured; for example, "high" ratings peaked 5 min after
injection, whereas "heavy or sluggish feeling" ratings peaked 60 to
120 min after injection. For comparison purposes, figure 2 also shows
scores from the 10 mg morphine condition. Time course and magnitude of
effects were similar between 10 mg morphine and 10 mg nalbuphine on the
three VAS scales.
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Drug Effects and Drug Liking. Nalbuphine.
Significant
Dose × Time increases were obtained on the "feel drug effect"
rating (P < .001) and the "like drug effect" rating (P < .001). "Feel drug effect" ratings were related to nalbuphine dose in an orderly fashion, and subjects still reported an effect at
300 min after injection with the 10-mg dose (fig. 3,
left frame). "Like Drug Effect" ratings increased in a dose-related
manner after nalbuphine injection, but the effect was transient,
i.e., significant only at the 5-min time-point (fig. 3,
right frame).
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Postsession Questionnaires. Nalbuphine. On the questionnaire that assessed residual effects of the drug, significant Dose effects were obtained with nalbuphine on five ratings: "feel bad" (P < .01), "headache" (P < .05), "heavy" (P < .05), "lightheaded" (P < .05) and "nausea" (P < .05), one of the two higher doses generally being responsible for the significant effects. On the multiple-choice drug preference questionnaire, significant Dose effects were found (P < 0.05), the 5-mg dose of nalbuphine having a significantly higher crossover point ($3.10) than the saline condition ($0.58).
Peak effects. Significant Dose effects were obtained on the following ratings: "clumsy" (P < .05), "feel bad" (P < .05), "heavy" (P < .01), "lightheaded" (P < .05) and "nausea" (P < .05). Both drugs increased "feel bad" ratings; morphine increased "clumsy" and "heavy" ratings; and 10 mg nalbuphine increased "nausea" ratings. Post-hoc testing revealed no differences between the two drug conditions and the saline condition on the rating of "lightheaded." On the drug preference questionnaire, no differences in preference (P = .15, not significant) existed between saline and the two active drug conditions (saline: $0.58; 10 mg nalbuphine: $2.38; 10 mg morphine: $2.28).Psychomotor Performance
Nalbuphine. Nalbuphine, in a dose-related manner,
induced exophoria on the Maddox Wing test (Dose × Time: P < .05) and decreased performance on the DSST (Dose × Time: P < .05; fig. 4). Peak impairment occurred on the DSST at
120 min after injection. Figure 4 also shows DSST performance from the
10 mg morphine condition: there was a significant decrease in number of
symbols drawn at the 120-min time-point when morphine was compared to
saline. Significant Nalbuphine Dose × Time effects were also
obtained on the memory test (P < .001), but the impairment in
cognitive performance was not dose-related (i.e., immediate
recall was affected at only the 2.5 and the 5.0 mg nalbuphine doses). A
significant Dose effect (P < .01) was obtained on number of
mistakes made on the eye-hand coordination test, but
post-hoc testing failed to reveal significant differences between the effect of saline and that of any of the three nalbuphine doses. Performance on the logical reasoning test and the auditory reaction time test were unaffected by nalbuphine.
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Peak or trough effects. Ten milligrams of nalbuphine had significantly greater trough effects on the number of symbols correctly drawn on the DSST (40.5 ± 2.0 symbols), and significantly greater peak effects on number of mistakes on the eye-hand coordination test (26.5 ± 2.1 mistakes), when compared with the saline conditions (DSST: 44.6 ± 2.1 symbols; eye-hand test: 21.7 ± 1.8 mistakes). Ten milligrams of morphine was not significantly different from saline on these two measures. Ten milligrams of nalbuphine and 10 mg morphine differed significantly from saline but not from each other on Maddox Wing performance (nalbuphine: 9.5 ± 1.4 prism diopters; morphine: 9.1 ± 1.4 prism diopters; saline: 4.9 ± 1.1 prism diopters).
Physiological Effects
Nalbuphine. Significant effects were obtained on HR
(Dose: P < .05), arterial oxygen saturation (Dose × Time:
P < .001), respiration rate (Dose × Time: P < .05)
and miosis (Dose × Time: P < .001). Although there was a
significant Dose effect for HR, post-hoc testing revealed
that the differences between the drug and saline conditions were not
significant. Neither decrease in arterial oxygen saturation rate nor
decreases in respiration rate were dose-related; rates were depressed
in the 2.5- and 10-mg dose conditions but not in the 5.0-mg dose
condition. Nalbuphine decreased pupil size in a dose-related fashion,
and pupil constriction was still evident 300 min after injection with
the 10-mg dose of nalbuphine (fig. 5). Ten milligrams of
morphine had miotic effects similar in time course and magnitude of
effect to those of 10 mg nalbuphine, except that morphine had
significantly greater miotic effects than 10 mg nalbuphine 300 min
after injection.
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Trough effects. Ten milligrams of nalbuphine and 10 mg morphine had significantly greater trough effects on pupil size when compared with the saline, but the magnitude of miosis did not differ between the two drug conditions. Trough pulse rate and respiration rate values were significantly lower in the 10 mg nalbuphine (pulse rate: 53.0 ± 1.7 bpm; respiration rate: 10.0 ± 0.5 breaths/min) and 10 mg morphine conditions (pulse rate: 52.7 ± 1.7 bpm; respiration rate: 9.9 ± 0.5 breaths/min) relative to the saline condition (pulse rate: 56.7 ± 1.4 bpm; respiration rate: 11.8 ± 0.8 breaths/min). Although there was a significant Dose effect for arterial oxygen saturation, post-hoc testing revealed no differences between the two drug conditions and the saline condition. Neither nalbuphine nor morphine affected systolic or diastolic blood pressure.
Adverse Effects
One subject vomited two times during a session in which 10 mg nalbuphine was given. He and two other subjects vomited within 24 h after the session in which 10 mg nalbuphine was administered. Two subjects vomited within 24 h after the session in which 10 mg morphine was administered. No other adverse effects, such as psychotomimesis, were reported during or after sessions.
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Nalbuphine in healthy volunteers at a dose range of 2.5 to 10 mg had orderly dose-related effects on mood, psychomotor performance, and physiology. Ten milligrams of nalbuphine produced similar effects on these variables to an equianalgesic dose of morphine (10 mg). The similarity in effects of these equianalgesic doses of nalbuphine and morphine is consistent with a number of other behavioral pharmacological studies that demonstrated similarities between the mixed agonist-antagonist nalbuphine and the full mu agonist morphine.
One weakness of the present study was that a full range of morphine doses was not tested in order that a more thorough characterization of the similarities and differences between morphine and nalbuphine could be made. One must therefore interpret the present results comparing nalbuphine to morphine with caution, remembering that those differences or similarities that were found may not exist with higher or lower doses. For example, the degree to which 2.5 or 5 mg of morphine resembles 2.5 or 5 mg of nalbuphine cannot be ascertained from the results of this study. What can be said with a greater degree of certainty is that at doses typically used for postoperative pain relief, 10 mg, morphine and nalbuphine appear to be alike on the measures obtained in this study.
Nalbuphine dose-related effects were obtained on most variables
measured, including miosis (see fig. 5). This stands in contrast to
some other human studies, in which ceiling effects have been obtained
on such measures as analgesia (Gal et al., 1982), subjective effects (Jasinski and Mansky, 1972), miosis (Jasinski and Mansky, 1972)
and respiratory depression (Romagnoli and Keats, 1980; Gal et
al., 1982). The difference between the present study and the other
studies is that the latter studies included the testing of higher doses
(e.g., 24-72 mg, injected). Our study was designed to
characterize effects of doses of nalbuphine that are commonly used in
clinical settings. Had higher doses of nalbuphine been tested in the
present study, ceiling effects on some or all of the dependent measures
might have been obtained.
In a recent study, the suggestion was made that nalbuphine resembles a
kappa agonist more than a mu agonist in opioid
abusers (Preston and Bigelow, 1994, p. 59). In that study, doses of
i.m. nalbuphine up to 24 mg/70 kg b.wt. resembled other mixed
agonist-antagonists in terms of both discriminative stimulus and
subjective effects. The results of the present study suggest that i.v.
nalbuphine up to doses of 10 mg/70 kg has a subjective effects profile
quite similar to that of a prototypic mu agonist (tables
2-4). The discrepancy may be related to the doses of nalbuphine tested
in various studies. For example, in the Preston and Bigelow (1994) drug
discrimination study, 6 mg of i.m. nalbuphine engendered both
hydromorphone-appropriate responding (approximately 60% operant
responding) and saline-appropriate responding (approximately 40%
operant responding), with no butorphanol-appropriate responding. At the
24-mg i.m. dose, 80% and 20% of responding were
butorphanol-appropriate and hydromorphone-appropriate responding, respectively. Thus nalbuphine was more hydromorphone-like at low doses
and more butorphanol-like at higher doses. By the same token, Jasinski
and Mansky (1972) observed that 8 mg of nalbuphine (s.c.) was similar
to morphine in terms of subjective effects. However, when the dose was
increased to 24 and 72 mg, the drug engendered effects dissimilar to
that of morphine but more similar to that of opioid drugs such as
nalorphine and cyclazocine. Elliott et al. (1970), using the
same comparatively low doses as those in the present study, noted
similar subjective effects between doses of morphine and nalbuphine in
opioid abusers. Finally, several clinical studies have directly
compared nalbuphine's side effects to mu agonist side
effects. The majority of these clinical studies, using relatively low
doses, indicate that the side-effect profile of nalbuphine resembles
that of mu agonists such as morphine and codeine, the
primary side effect being sedation or drowsiness (Beaver and Feise,
1978; Okun, 1982; Bahar et al., 1985; Dolan et
al., 1988; Fee et al., 1989). All of these results,
including those taken from opioid-abusing and non-opioid abusing
volunteer and patient studies, suggest that the degree to which
nalbuphine resembles morphine depends on the doses that are being
tested. At lower doses the effects of nalbuphine are similar, and at
higher doses are dissimilar, to the effects of morphine.
Psychomotor performance, as measured by DSST performance, was disrupted
by nalbuphine. Memory impairment was not related to nalbuphine dose and
was found only on measures of immediate recall, not on measures of
delayed recall. It is not clear, then, whether nalbuphine at doses of
10 mg or lower impairs memory in any consistent manner. When peak and
trough effects of 10 mg nalbuphine were compared to those of 10 mg
morphine and saline, nalbuphine but not morphine impaired DSST
performance and eye-hand coordination. However, other studies have
shown impairment by 10 mg morphine (e.g., Zacny et
al., 1994a), and in fact, in the present study, when compared with
saline, DSST performance was impaired by 10 mg morphine 2 h after
its injection. Further, both drugs at a 10-mg dose induced exophoria,
which is considered a relatively gross indicator of psychomotor
impairment (i.e., those drugs that induce exophoria or
extraocular muscle imbalance also tend to produce other kinds of
impairment). Therefore, we suggest from the data that the two drugs, at
the doses tested, appear to be fairly similar in propensity to induce
impairment. It should be noted that drug history seems to play a role
in the degree to which impairment occurs with these opioids; neither
nalbuphine nor hydromorphone (an opioid similar in effects to morphine)
in opioid abusers has impaired psychomotor performance, as measured by
the DSST (Preston et al., 1989a,b, 1990, 1992; Preston and Bigelow, 1994).
The results of this study contrast to those of a recent study in which
a dose of butorphanol (2 mg/70 kg) was compared with an equianalgesic
dose of morphine (10 mg/70 kg) (Zacny et al., 1994b). In
that study, a number of differences existed between the two drugs at
the tested i.v. doses: the subjective effects of 2 mg butorphanol and
10 mg morphine were qualitatively the same, but 2 mg butorphanol had a
larger magnitude of effect than 10 mg morphine (e.g., larger
VAS ratings of "coasting or spaced out," "drunken,"
"lightheaded"). Two milligrams of butorphanol also induced
subjective effects that 10 mg morphine did not; subjects reported
increased ratings of "confused," "difficulty concentrating," "dreamy," "floating" and "stimulated" after butorphanol,
but not after morphine, administration. However, in the present study, the majority of subjective effects reported after administration of 10 mg morphine were also reported after administration of 10 mg
nalbuphine, with a similar magnitude of effect. It appears, then, that
at equianalgesic doses, the profiles of subjective effects of the two
mixed agonist-antagonists nalbuphine (10 mg) and butorphanol (2 mg)
differ in the degree to which they resemble the profile of the
prototypic mu agonist opioid morphine (10 mg).
An interesting finding in this study was that nalbuphine had positive subjective effects, as measured by several different measures. First, subjects reported liking the effects of nalbuphine in a dose-related manner. Second, peak MBG scores were significantly greater in the 10 mg nalbuphine condition than in the saline condition. Third, VAS ratings of "having pleasant bodily sensations" were increased by nalbuphine, relative to saline. Taken together, these data suggest that nalbuphine might have reinforcing effects in non-opioid abusers. Finally, in the postsession multiple-choice preference questionnaire, subjects self-reported that they would forego, on average, $3.10 for an injection of 5 mg of nalbuphine and $0.58 for an injection of saline (at the time of this rating, subjects did not know what drug they had actually received). This questionnaire is designed to assess the reinforcing effects of drugs, but in the present study, it was used as an indicator of drug liking. Further studies need to be conducted with this questionnaire, to determine the conditions in which it has utility in characterizing the abuse liability of drugs in non-drug abusing volunteers.
In conclusion, we have characterized the subjective, psychomotor, and physiological effects of nalbuphine. Other studies have definitively characterized such effects of nalbuphine in opioid abusers. What distinguishes the present study from the others is the use of non-opioid abusing volunteers. At the doses tested, nalbuphine produced dose-related alterations in subjective effects and pupil size and induced impaired psychomotor performance. Ten milligrams of nalbuphine was also compared with and contrasted to an equianalgesic dose of morphine, 10 mg. The profiles of subjective and physiological effects were similar for 10 mg nalbuphine and 10 mg morphine. Determining whether morphine and nalbuphine produce a similar profile of effects at other doses awaits further study.
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Footnotes |
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Accepted for publication November 4, 1996.
Received for publication June 5, 1996.
1 Research was supported in part by Grant DA-08573 from the National Institute on Drug Abuse. We thank Drs. Christopher Young, Jerome Klafta, P. Allan Klock, and Mary Maurer, C.R.N.A., and Robert Shaughnessy, C.R.N.A., for their assistance in administering the drugs and monitoring the physiological status of the subjects.
Send reprint requests to: James P. Zacny, Department of Anesthesia & Critical Care/MC4028, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637.
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Abbreviations |
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ARCI, Addiction Research Center Inventory; PCAG, Pentobarbital-Chlorpromazine-Alcohol Group; BG, Benzedrine Group; LSD, Lysergic Acid Diethylamide; MBG, Morphine-Benzedrine Group; AMP, Amphetamine; DSST, Digit Symbol Substitution Test; VAS, Visual Analogue Scale; OAC, Opiate Adjective Checklist; SDQ, Single Dose Questionnaire.
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References |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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a preliminary report.
Psychopharmacol. Bull.
9: 13-17, 1973[Medline].
), 2.5 (
), 5.0 (
) and 10 mg/70 kg (
) nalbuphine on scores from the PCAG (left
frame), BG (middle frame) and LSD (right frame) scales of the ARCI. For purposes of comparison to 10 mg nalbuphine, 10 mg morphine (
) is
also shown on the graph. Each point is the mean across 16 subjects. Time-point 0 refers to effects measured immediately before the injection. Asterisks on the PCAG graph (in which a significant Dose × Time effect was obtained) indicate that a nalbuphine dose is significantly different from saline at a given time-point (Tukey post-hoc test; P < .05). Tukey testing was not done on
the BG and LSD data, because significant Dose × Time effects were
not obtained with these scales. The ranges of possible scores on the PCAG, BG and LSD scales are 0 to 15, 0 to 9 and 0 to 14, respectively.
