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Study Design Normal Quasi & Non Experimental Patients with Postoperative Pain Discussion

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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 ...
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Running Head: PATIENTS WITH POSTOPERATIVE PAIN

PATIENTS WITH POSTOPERATIVE PAIN
Name of Student
School name
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PATIENTS WITH POSTOPERATIVE PAIN

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PATIENTS WITH POSTOPERATIVE PAIN
1. Was the study design Experimental, Quasi-experimental or Non-experimental? How
do you know?
The study result was an experimental design. An experimental design is known to give a very high
level of control and reliability. This study is the first placebo-controlled, dose-response evaluation of a kopioid for the treatment of clinical pain. All doses of nalbuphine produced better responses in women
than in men confirming our previous findings of a gender difference in the e...

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