Study Design Normal Quasi & Non Experimental Patients with Postoperative Pain Discussion Please, checkout the uploaded file below, where you will find info

Study Design Normal Quasi & Non Experimental Patients with Postoperative Pain Discussion Please, checkout the uploaded file below, where you will find information and instructions. Pain 83 (1999) 339±345
www.elsevier.nl/locate/pain
The kappa opioid nalbuphine produces gender- and dose-dependent
analgesia and antianalgesia in patients with postoperative pain
Robert W. Gear a,b, Christine Miaskowski c, Newton C. Gordon b, Steven M. Paul c,d,
Philip H. Heller h, Jon D. Levine b,e,f,g,*
a
Center for Orofacial Pain, University of California, San Francisco, CA 94143, USA
Department of Oral and Maxillofacial Surgery, University of California, San Francisco, CA 94143, USA
c
Department of Physiological Nursing, University of California, San Francisco, CA 94143, USA
d
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143, USA
e
Department of Medicine, University of California, San Francisco, CA 94143, USA
f
Department of Anatomy, University of California, San Francisco, CA 94143, USA
g
Graduate Program in Neuroscience, University of California, San Francisco, CA 94143, USA
h
Kaiser Foundation Hospital, Hayward, CA 94545, USA
b
Received 3 December 1998; received in revised form 7 April 1999; accepted 26 May 1999
Abstract
Nalbuphine, pentazocine, and butorphanol, mixed agonist/antagonist opioids that induce analgesia by acting predominantly at kappa
opioid receptors, have recently been shown in single-dose studies to have greater analgesic ef®cacy in women than in men. In the current
experiments, the ®rst placebo controlled dose response study of opioid analgesic ef®cacy that examines for gender differences, nalbuphine (5,
10, or 20 mg) and placebo were evaluated in 62 men and 69 women for the treatment of moderate to severe postoperative pain following
extraction of impacted wisdom teeth. In a randomized, open injection, double blind experimental design, pain intensity was recorded on a 10
cm visual analog scale (VAS) immediately prior to drug administration (baseline) and at 20 min intervals thereafter. Although responses to
placebo were similar in men and women, for all doses of nalbuphine women exhibited signi®cantly greater analgesic response than men,
compatible with our previous results. Unexpectedly, men receiving the 5 mg dose of nalbuphine experienced signi®cantly greater pain than
those receiving placebo; only the 20 mg dose of nalbuphine in men produced signi®cant analgesia compared to placebo. While a similar
antianalgesic effect was not observed in women, only the 10 mg dose of nalbuphine produced signi®cant analgesia compared to placebo.
These results suggest that the optimal analgesic dose of nalbuphine for women is lower than the highest dose that can be safely administered.
In contrast, the antianalgesic effect of nalbuphine suggests avoidance of its routine use for postoperative analgesia in men until further studies
clarify this issue. Because gender differences in other mixed kappa agonists/antagonists (i.e. pentazocine and butorphanol) have previously
been shown, these results may generally apply to this class of opioid analgesics. q 1999 International Association for the Study of Pain.
Published by Elsevier Science B.V.
Keywords: Opioids; Dose response; Placebo; Men; Women; Third molars
1. Introduction
Although gender differences in responses to experimental
pain stimuli and in the prevalence of clinical pain
syndromes have been reported in many studies, (see Fillingim and Maixner, 1995; Unruh, 1996, for reviews), only
recently have gender differences in analgesic responses to
opioids been evaluated. In an earlier study involving admin* Corresponding author. NIH Pain Center, Levine Research Unit, Box
0440, 521 Parnassus Avenue, Room C-522, University of California San
Francisco, CA 94143-0440, USA. Tel.: 11-415-476-5108; fax: 11-415476-6305.
E-mail address: levine@itsa.ucsf.edu (J.D. Levine)
istration of opioids in combination with an adjuvant, it
appeared that pentazocine, an opioid agonist/antagonist
which produces analgesia by predominantly k -action,
provided signi®cantly greater analgesia in women (Gordon
et al., 1995). Therefore, subsequent studies were designed to
compare the analgesic responses of men and women to a
single dose of pentazocine (Gear et al., 1996a) as well as
butorphanol or nalbuphine (Gear et al., 1996b). These
agents, referred to as k -opioids because they are thought
to produce analgesia by an agonist action at k -receptors,
are agonist/antagonists in that they also exert agonist action
at s -receptors, which produce dysphoria but lack analgesic
activity, and antagonist action at m-receptors (Zola and
0304-3959/99/$20.00 q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V.
PII: S 0304-395 9(99)00119-0
340
R.W. Gear et al. / Pain 83 (1999) 339±345
McLeod, 1983; Jaffee and Martin, 1990). Subjects were
patients experiencing moderate to severe postoperative
pain after the removal of bony impacted mandibular third
molars. Each of these k -opioids induced signi®cantly
greater analgesia in women than in men at the doses used.
The current study was performed to determine whether,
within the range of doses usually given in clinical practice,
the observed gender differences in analgesia produced by
this class of opioids is due to the presence of a rightward
shift in the dose-response relationship of men compared to
women. Speci®cally, we tested the hypothesis that men,
given a suf®ciently large dose of nalbuphine, would experience analgesia equivalent to that observed in women. Since
there are no previous placebo controlled dose response
studies of the analgesic ef®cacy of this class of opioids,
we compared the analgesic responses produced by nalbuphine with those produced by placebo within each gender.
Furthermore, since placebo analgesia is likely to be
mediated, at least in part, by an endogenous opioid (Levine
et al., 1978; Grevert et al., 1983; Hersh et al., 1993; Benedetti, 1996), this experimental design also allowed us to
determine if there are gender differences in placebo
responses. Therefore, different groups of male and female
patients experiencing moderate to severe postoperative
dental pain were administered either a placebo (0.9% saline)
or one of three doses (5, 10, or 20 mg) of nalbuphine.
mined using a two-way analysis of variance (ANOVA). A
three-way repeated measures ANOVA with two between
subjects factors (i.e. gender with two levels and dose with
four levels) and one within subjects factor (i.e. time with
nine levels) was used to determine if there were signi®cant
(P , 0:05) differences in analgesic responses among the
eight gender/drug groups. To examine the analgesic ef®cacy
of nalbuphine for women, a two-way ANOVA with one
between subjects factor (i.e. dose with four levels) and
one within-subjects factor (i.e. time with nine levels) was
performed, and this analysis was followed by further posthoc contrasts for each dose of nalbuphine compared to
placebo (see below). Similar analyses were performed for
men. Additional analyses were employed to determine
whether women differed signi®cantly from men in their
responses to placebo and to each dose of nalbuphine.
The demographic characteristics of the patient groups are
provided in Table 1. Since men weighed more than women,
weight was included as a covariate in all subsequent
analyses. Differences between men and women in baseline
intensity scores were accounted for by calculating patient
responses as changes from baseline pain intensity.
This study was approved by the Committee on Human
Research at the University of California at San Francisco.
2. Materials and methods
3.1. Gender differences in analgesic responses to various
doses of nalbuphine or placebo
In this clinical trial, 131 patients underwent standardized
surgery by the same oral surgeon for removal of third molar
teeth including at least one bony impacted mandibular third
molar (Levine and Gordon, 1984; Levine et al., 1988). Prior
to surgery, patients received intravenous diazepam, nitrous
oxide, and a local anesthetic (mepivacaine without vasoconstrictor to obtain a nerve block of short duration). The duration of the experiment, measured from the time of
administration of the test drug, was 3 h. After surgery,
each patient was randomly assigned to receive, in an
open, double blinded fashion, through an intravenous line,
an injection of either placebo (0.9% saline) or nalbuphine
(5, 10, or 20 mg; Abbott Laboratories, Abbott Park, IL).
Criteria for administration of the test drug were: (1) elapse
of a period of at least 80 min after the onset of the local
anesthetic and (2) a pain rating that was greater than one
quarter (2.5 cm) of the maximum possible visual analog
scale (VAS) rating (10 cm). Baseline pain intensity was
de®ned as the VAS pain rating just before administration
of the test drug. The magnitude of the analgesic response for
each patient was de®ned as the difference between the pain
rating at each time point following test drug administration
and the baseline VAS pain rating.
2.1. Data analysis
Differences in demographic characteristics were deter-
3. Results
The three-way repeated measures ANOVA, with two
between subjects factors and one within subjects factor,
demonstrated signi®cant main effects of gender
(F 1; 130† ˆ 7:7, P , 0:01), drug group (F 3; 130† ˆ 4:3,
P , 0:01), and time (F 8; 1048† ˆ 18:9, P , 0:0001), as
well as signi®cant gender x time (F 8; 1048† ˆ 7:5,
P , 0:0001) and gender £ drug group £ time interactions
(F 24; 1048† ˆ 1:7, P , 0:02). These results indicate that,
overall, women experienced better responses than did men,
that the responses of the participants were signi®cantly
different depending on the dose of nalbuphine or placebo
administered, that, overall, analgesic responses changed
over the 3 h of the experiment, that the time courses of
the responses of men and women were signi®cantly different, and that either the gender £ time interaction depended
on the dose of the drug administered or that the drug group £
time interaction depended on the participant’s gender. Both
of these interpretations were evaluated using post-hoc
contrasts.
3.2. Ef®cacy of nalbuphine compared to placebo
In order to determine if the analgesic responses to the
three doses of nalbuphine and placebo differ signi®cantly
in women, a two-way repeated measures ANOVA with one
between subjects’ factor (i.e. drug dose with four levels) and
Nalbuphine (10 mg)
14
Nalbuphine (20 mg)
22
2.45
1.13
0.03
0.22
6.47
0.49
SEM
56.92
22.93
0.41
4.30
84.29
6.46
Mean
3.14
1.05
0.04
0.20
8.76
0.73
SEM
56.71
22.32
0.42
4.38
72.73
5.80
Mean
1.48
0.78
0.02
0.19
1.99
0.41
SEM
74.00
24.69
0.40
4.08
81.25
5.03
2.97
0.76
0.03
0.22
4.82
0.49
72.55
22.80
0.40
4.25
98.0
3.69
Mean SEM Mean
4.74
1.58
0.02
0.17
13.36
0.32
SEM
Nalbuphine (5 mg)
15
76.21
25.47
0.34
4.15
72.67
4.49
Mean
3.00
1.31
0.03
0.28
1.82
0.56
SEM
Nalbuphine (10 mg)
15
70.82
22.63
0.38
4.27
73.75
3.68
Mean
2.19
0.99
0.02
0.18
3.75
0.34
SEM
Nalbuphine (20 mg)
16
a
Characteristics of study participants. Surgical severity scores were assigned as follows: Upper third molar extractions: uncomplicated or tissue impacted teeth ˆ 0.25, partial or full bony impacted teeth ˆ 0.50.
Lower third molar extractions: uncomplicated or tissue impacted teeth ˆ 1, partial or full bony impacted teeth ˆ 2. The surgical severity score for each patient is the sum of the assigned values for each extracted
tooth (Faucett et al., 1994).
b
Indicate signi®cant differences between groups.
58.91
23.50
0.41
3.81
83.33
5.02
Mean SEM Mean
Placebo
16
Nalbuphine (5 mg)
18
Placebo
15
Weight (kg) b
55.86 1.96
Age (years)
22.67 1.04
Valium (mg/kg)
0.35 0.03
Surgical severity
4.35 0.22
Time to drug administration 72.67 2.67
Baseline VAS b
6.01 0.69
# Participants
Men
Women
Table 1
Study participant sample characteristics a
R.W. Gear et al. / Pain 83 (1999) 339±345
341
342
R.W. Gear et al. / Pain 83 (1999) 339±345
Fig. 1. The effect on postoperative pain of various doses of nalbuphine compared to placebo in women (panels A±C) or men (panels D±E) plotted as change in
postoperative pain level over the 3 h following administration (see legend in ®gure). `Change in pain level’ (ordinate), recorded on a 10 cm visual analog scale
(VAS), represents changes from baseline level (represented by the horizontal dotted lines) after various times. Decreased pain scores (i.e. analgesia) are above
the baseline. See Table 1 for number of study participants in each group. Data are plotted as mean ^ SEM in this and Fig. 2.
one within subjects factor (i.e. time with nine levels) was
performed. A similar analysis was performed for men.
These analyses were undertaken to determine how the
drug dose £ time interaction was dependent on gender.
3.2.1. Women
For women, this analysis demonstrated only a signi®cant
main effect of drug group (F 3; 68† ˆ 3:5, P , 0:02), indicating that there were signi®cant differences in the effects of
different doses of nalbuphine and placebo. Post-hoc
contrasts, comparing each dose of nalbuphine to placebo;
for these analyses signi®cant difference was de®ned as P ,
0:0167 (i.e. 0:05 4 3).
The ®rst contrast, comparing the responses of women
who received 5 mg of nalbuphine to placebo, demonstrated
only a signi®cant main effect of time (F 8; 264† ˆ 2:8,
P , 0:006), indicating that the responses of the women in
these two groups changed over time but that there were no
signi®cant differences in the effects of this dose of nalbuphine compared to placebo (Fig. 1A).
The second contrast, comparing the responses of women
who received 10 mg of nalbuphine to placebo, demonstrated
a signi®cant main effect of drug group (F 1; 28† ˆ 9:9,
P , 0:004) as well as a signi®cant drug group £ time interaction (F 8; 232† ˆ 2:4, P , 0:0167) indicating that the
responses of women who received this dose of nalbuphine
were signi®cantly greater and lasted signi®cantly longer
than those who received placebo (Fig. 1B).
The third contrast, comparing the responses of women
who received 20 mg of nalbuphine to placebo, demonstrated
R.W. Gear et al. / Pain 83 (1999) 339±345
343
Fig. 2. The effect of placebo or various doses of nalbuphine on postoperative pain in women and men plotted as change in postoperative pain level over the 3 h
following administration (see legend in Fig. 1).
no signi®cant main or interaction effects. These results indicate that there were no signi®cant differences in the effects
of this dose of nalbuphine compared to placebo (Fig. 1C).
Taken together, these results indicate that in the women
only the 10 mg dose of nalbuphine produced signi®cant
analgesia compared to placebo.
3.2.2. Men
For men, the ANOVA demonstrated a signi®cant main
effect of time (F 9; 496† ˆ 22:6, P , 0:0001) and a signi®cant drug group £ time interaction (F 24; 496† ˆ 2:1,
P , 0:01) indicating that the responses of the men changed
over time and that the differences among the four drug
groups were dependent on time. As was done for analysis
of the data for women, post hoc contrasts comparing each
dose of nalbuphine to placebo were performed with a pvalue set at 0.0167 (i.e. 0:05 4 3).
The ®rst contrast, comparing the responses of men who
received 5 mg of nalbuphine to placebo, demonstrated a
signi®cant main effect of time (F 8; 248† ˆ 9:7,
P , 0:0001) and a signi®cant drug group £ time interaction
(F 8; 248† ˆ 5:2, P , 0:0001) indicating that the responses
of the men changed over time and that the increasing pain
reported by men who received this dose of nalbuphine was
signi®cantly different from placebo (Fig. 1D).
The second contrast, comparing the responses of men
who received 10 mg of nalbuphine to placebo, demonstrated
only a signi®cant main effect of time (F 9; 248† ˆ 4:9,
P , 0:0001), indicating that the responses of men changed
over time but that the effects of this dose of nalbuphine were
not signi®cantly different from placebo (Fig. 1E).
The third contrast, comparing the responses of men who
received the 20 mg of nalbuphine to placebo, demonstrated
a signi®cant main effect of time (F 8; 256† ˆ 7:1,
P , 0:001) and a signi®cant drug group £ time interaction
(F 8; 256† ˆ 2:5, P , 0:0167) indicating that the responses
of men changed over time and that this dose of nalbuphine
was signi®cantly more analgesic than placebo (Fig. 1F).
Taken together, these results suggest that in men the 5 mg
of nalbuphine produced signi®cantly increased pain
compared to placebo, that the effect of 10 mg of nalbuphine
was not signi®cantly different from placebo, and that 20 mg
of nalbuphine produced a short-lived signi®cant analgesia
compared to placebo.
3.3. Gender differences in responses to placebo and
different doses of nalbuphine
In order to determine if the responses to placebo differ
signi®cantly between men and women, a two-way repeated
measures ANOVA with one between subjects factor (i.e.
gender with two levels) and one within subjects’ factor
(i.e. time with nine levels) was performed. Similar analyses
were performed for each dose of nalbuphine. The analyses
were undertaken to determine how the gender £ time interaction was dependent on drug dose.
3.3.1. Placebo
The ANOVA demonstrated a signi®cant main effect of
time (F 8; 248† ˆ 2:2, P , 0:03), but no signi®cant main
effect of gender or signi®cant gender £ time interaction,
indicating that the responses of participants who received
placebo changed over time, but that there were no signi®cant gender differences in responses to placebo (Fig. 2A).
3.3.2. 5 mg dose of nalbuphine
The ANOVA demonstrated signi®cant main effects of
time (F 8; 264† ˆ 13:6, P , 0:0001), and gender
(F 1; 32† ˆ 4:3, P , 0:05), and a signi®cant gender £
time interaction (F 8; 264† ˆ 4:3, P , 0:0001) indicating
that responses changed over time, that women experienced
signi®cantly better responses at this dose level than did men,
344
R.W. Gear et al. / Pain 83 (1999) 339±345
and that the differences in analgesic responses between men
and women were dependent on time (Fig. 2B).
3.3.3. 10 mg dose of nalbuphine
The ANOVA demonstrated signi®cant main effects of
time (F 8; 232† ˆ 4:9, P , 0:0001), and gender
(F 1; 28† ˆ 8:3, P , 0:01), and a signi®cant gender £
time interaction (F 8; 240† ˆ 4:2, P , 0:0001) indicating
that analgesic responses changed over time, that women
experienced signi®cantly greater analgesia than men, and
that the differences in responses between men and women
were dependent on time (Fig. 2C).
3.3.4. 20 mg dose of nalbuphine
The ANOVA demonstrated a signi®cant main effect of
time (F 8; 304† ˆ 7:0, P , 0:0001), and a signi®cant
gender £ time interaction (F 8; 304† ˆ 3:1, P , 0:002)
indicating that the analgesic responses changed over time
and that the differences in analgesic responses between men
and women were dependent on time (Fig. 2D).
4. Discussion
This study is the ®rst placebo-controlled, dose-response
evaluation of a k -opioid for the treatment of clinical pain.
All doses of nalbuphine produced better responses in
women than in men con®rming our previous ®ndings of a
gender difference in the ef®cacy of k -opioids (Gordon et al.,
1995; Gear et al., 1996a,b). Placebo responses did not differ
signi®cantly between men and women strongly suggesting
that the observed gender differences in responses to nalbuphine were not due to a non-speci®c effect of drug administration or to gender differences in response to drugs given
as part of the surgical protocol (e.g. diazepam).
There was a striking unexpected signi®cant increase in
pain (anti-analgesia) reported by men who received the 5
mg dose of nalbuphine. Men who received either 10 or 20
mg of the drug reported a short-lived decrease in pain intensity scores with only the 20 mg dose producing responses
that were signi®cantly different from placebo. Thus, our
hypothesis that administration of a suf®ciently large dose
of nalbuphine to males would evoke an analgesic response
similar to …
Purchase answer to see full
attachment

Don't use plagiarized sources. Get Your Custom Essay on
Study Design Normal Quasi & Non Experimental Patients with Postoperative Pain Discussion Please, checkout the uploaded file below, where you will find info
Just from $13/Page
Order Essay
Homework Writings Pro
Calculate your paper price
Pages (550 words)
Approximate price: -

Why should I choose Homework Writings Pro as my essay writing service?

We Follow Instructions and Give Quality Papers

We are strict in following paper instructions. You are welcome to provide directions to your writer, who will follow it as a law in customizing your paper. Quality is guaranteed! Every paper is carefully checked before delivery. Our writers are professionals and always deliver the highest quality work.

Professional and Experienced Academic Writers

We have a team of professional writers with experience in academic and business writing. Many are native speakers and able to perform any task for which you need help.

Reasonable Prices and Free Unlimited Revisions

Typical student budget? No problem. Affordable rates, generous discounts - the more you order, the more you save. We reward loyalty and welcome new customers. Furthermore, if you think we missed something, please send your order for a free review. You can do this yourself by logging into your personal account or by contacting our support..

Essay Delivered On Time and 100% Money-Back-Guarantee

Your essay will arrive on time, or even before your deadline – even if you request your paper within hours. You won’t be kept waiting, so relax and work on other tasks.We also guatantee a refund in case you decide to cancel your order.

100% Original Essay and Confidentiality

Anti-plagiarism policy. The authenticity of each essay is carefully checked, resulting in truly unique works. Our collaboration is a secret kept safe with us. We only need your email address to send you a unique username and password. We never share personal customer information.

24/7 Customer Support

We recognize that people around the world use our services in different time zones, so we have a support team that is happy to help you use our service. Our writing service has a 24/7 support policy. Contact us and discover all the details that may interest you!

Try it now!

Calculate the price of your order

Total price:
$0.00

How it works?

Follow these simple steps to get your paper done

Place your order

Fill in the order form and provide all details of your assignment.

Proceed with the payment

Choose the payment system that suits you most.

Receive the final file

Once your paper is ready, we will email it to you.

Our Services

Our reputation for excellence in providing professional tailor-made essay writing services to students of different academic levels is the best proof of our reliability and quality of service we offer.

Essays

Essay Writing Service

When using our academic writing services, you can get help with different types of work including college essays, research articles, writing, essay writing, various academic reports, book reports and so on. Whatever your task, homeworkwritingspro.com has experienced specialists qualified enough to handle it professionally.

Admissions

Admission Essays & Business Writing Help

An admission essay is an essay or other written statement by a candidate, often a potential student enrolling in a college, university, or graduate school. You can be rest assurred that through our service we will write the best admission essay for you.

Reviews

Editing Support

Our professional editor will check your grammar to make sure it is free from errors. You can rest assured that we will do our best to provide you with a piece of dignified academic writing. Homeworkwritingpro experts can manage any assignment in any academic field.

Reviews

Revision Support

If you think your paper could be improved, you can request a review. In this case, your paper will be checked by the writer or assigned to an editor. You can use this option as many times as you see fit. This is free because we want you to be completely satisfied with the service offered.