Newton C. Gordon

The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain

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 efficacy in women than in men. In the current experiments, the first placebo controlled dose response study of opioid analgesic efficacy 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 significantly greater analgesic response than men, compatible with our previous results. Unexpectedly, men receiving the 5 mg dose of nalbuphine experienced significantly greater pain than those receiving placebo; only the 20 mg dose of nalbuphine in men produced significant analgesia compared to placebo. While a similar antianalgesic effect was not observed in women, only the 10 mg dose of nalbuphine produced significant 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.

Gender difference in analgesic response to the kappa-opioid pentazocine ☆

Gender difference in analgesia produced by the kappa-opiate pentazocine was investigated in a model of post-operative dental pain. In a recent study [Gordon et al., Neuroscience, 69 (1995) 345-349.] evaluating interaction between the GABAB agonist baclofen and opiates with respect to postoperative analgesia we found that females receiving pentazocine for the treatment of postoperative pain showed better analgesia than did males receiving similar treatment. To follow-up this result, we evaluated for the effect of gender on analgesia produced by pentazocine administered to participants not receiving another experimental medication. The analgesic response to pentazocine in ten females was compared to that in eight males. All participants were administered pentazocine after undergoing surgery for the removal of impacted third molars. We confirm our previous finding that pentazocine produces significantly greater analgesia in females than in males; no significant difference was observed in analgesia among females in different phases of the menstrual cycle.

Differences in postoperative pain severity among four ethnic groups

Subjects (N = 543) reporting on acute postoperative dental pain were classified into four major ancestral groups: Asian (N = 96), black American (N = 65), European (N = 296), and Latino (N = 88). Pain severity was measured using a 10-cm visual analogue scale following a standardized operative procedure. The subjects of European descent reported significantly less severe pain than those of black American or Latino descent. They also reported less pain than Asians, although this finding did not reach significance. Evaluation of covariates, including gender, age, education, generation in the United States, and difficulty of the surgical extraction, demonstrated that gender was significant, with men reporting less pain than women regardless of ancestry. Possible implications of these findings are discussed in terms of potential differences in physiology, in addition to social learning.

Analgesic responses to morphine and placebo in individuals with postoperative pain

Abstract The effects of placebo and varying doses of intravenous morphine were studied in 74 patients. All patients underwent extraction of impacted mandibular third molars. Two hours after onset of anesthesia all patients received a placebo (intravenous saline). One hour after the placebo administration each patient received either a second placebo or, 4, 6, 8 or 12 mg of morphine, double blind, via a hidden intravenous line. Pain level was evaluated 50 min after morphine administration using a visual analog scale. Pooled data from all patients produced a dose‐response curve asymptotic by 8 mg. The mean pain relief following the second placebo was found to be between that obtained following hidden administration of 4 and 6 mg of morphine. When pain level reports for individuals were plotted two unexpected features appeared. First, no patient reported complete relief, even at the highest dose of morphine (12 mg). Second, pain level reports 50 min following each dose of morphine tended to be in two clusters. Within each cluster the average pain was independent of the dose of morphine administered. However, in groups receiving progressively higher doses of morphine, the percentage of patients within the low pain level cluster increased. These latter observations are most consistent with the concept that there is a step component for narcotic analgesia.

Benzodiazepine mediated antagonism of opioid analgesia

Abstract Activation of supraspinal &ggr;‐aminobutyric acid‐A (GABAA) receptors is known to result in antagonism of opioid analgesia. Since benzodiazepines enhance the action of GABA at GABAA receptors, we hypothesized that administration of these agents for preoperative sedation might antagonize the analgesic effects of opioids administered postoperatively. If so, then administration of the benzodiazepine antagonist flumazenil should enhance postoperative morphine analgesia. In a double‐blind, placebo‐controlled study of patients who received a preoperatively administered benzodiazepine (diazepam) for sedation and a postoperatively administered opioid (morphine) for analgesia, we investigated opioid‐benzodiazepine interactions affecting postoperative dental pain. We found that flumazenil significantly enhanced morphine analgesia consistent with the hypothesis that the preoperatively administered benzodiazepine exerts an ongoing antianalgesic effect. In addition, we followed these patients over the first and second postoperative days to determine if there were differences between the drug groups in post‐discharge pain, analgesic consumption, or side‐effects. Participants receiving flumazenil reported significantly less post‐discharge nausea and used significantly less ibuprofen. Since post‐discharge pain levels were not significantly different, these results suggest that the patients receiving flumazenil required less analgesic medication to achieve a comparable level of pain control. In summary, our results indicate that the benzodiazepine antagonist flumazenil enhances morphine analgesia and decreases post‐discharge side‐effects as well as post‐discharge need for analgesic medication.

Enhancement of morphine analgesia by the GABAB agonist baclofen

Opioid-GABAergic interactions for the treatment of post-operative pain were investigated in two double-blind, placebo-controlled experiments. We first studied the effect of pre-operatively administered baclofen, a GABAB receptor agonist, on the analgesia produced by intravenously administered morphine, a predominantly mu-opioid analgesic. In a separate trial, we studied the effect of baclofen on the analgesia produced by pentazocine, a predominantly kappa-opioid analgesic. While baclofen alone did not affect the level of post-operative pain, morphine analgesia was significantly enhanced by baclofen compared to placebo. In contrast, baclofen did not affect the level of pentazocine analgesia: however, females receiving pentazocine showed significantly greater analgesia than males.

Fixation of mandibular fractures: A comparative analysis of rigid internal fixation and standard fixation techniques

This study used a prospective design to compare standard therapy (closed or open reduction with 4 weeks of maxillomandibular fixation) to rigid internal fixation (RIF) for the treatment of mandibular fractures. Ninety-two patients with 143 fractures were evaluated and treated. There was no statistically significant difference in the treatment results between the two groups, despite a bias in the distribution of study variables that favored the standard therapy.

Desipramine enhances opiate postoperative analgesia

&NA; In a double‐blind, placebo‐controlled study the analgesic efficacy of the combination of a tricyclic antidepressant and morphine was investigated. One of two tricyclic antidepressants (either amitriptyline, a relatively selective serotonin uptake inhibitor or desipramine, a relatively selective noradrenaline uptake inhibitor) or a placebo, was given for 1 week prior to surgery, followed by a single postoperative dose of morphine. Desipramine, but not amitriptyline, both increased and prolonged morphine analgesia. Neither tricyclic antidepressant reduced dental postoperative pain in the absence of morphine. We propose that desipramine enhances opiate analgesia by enhancing a noradrenergic component that contributes to endogenous opioid‐mediated analgesia systems.

Post-operative pain: effect of extent of injury and attention.

The relationship to pain level of extent of injury (as measured by number of teeth extracted) and attention paid to the injury (as measured by frequency of pain ratings) was studied in patients with dental postoperative pain. Patients had either 2 or 4 impacted wisdom teeth removed and rated their pain either 2 or 5 times during the experiment. A positive correlation was found between extent of injury and reported pain level as well as between frequency of pain rating and pain level. The correlation between frequency of pain rating and pain level was found only in patients with 4 teeth extracted. To our knowledge, this is the first study which quantitatively evaluates the relationship between amount of injury and level of pain. This study also suggests that the degree to which manipulations of psychological variables alter an individuals pain perception may depend on the extent of injury.

Pain in prelingual children and its evaluation by pain-induced vocalization

The medical evaluation of pain in the prelingual child is a major diagnostic challenge for even the most experienced clinician. Except for eye to eye communication, the only way an infant can signal information is by vocalizing. In the infant, the characteristic response to a noxious stimulus is a diffuse bodily movement accompanied by crying and, less consistently, reflex withdrawal [44,55,56]. In an infant whose noxious stimulus is internal, only the cry may be apparent. Although infants a few hours or days old may show no overt response to cutaneous irritation such as pin-prick, all will respond to deep pressure [44]. The accurate assessment of the intensity of pain and the adequacy of analgesia in prelingual patients is a major problem in pediatrics. Its importance is further suggested by the finding that early pain experience may influence later behavior [46,60]. Pain-induced vocalization (PIV) has been studied in a number of mammalian species, and such studies appear to offer a useful model for understanding pain-related behavior in the prelingual child. Spectrographic analysis of vocalization in infants has confirmed the general impression that cries of stress, pain and hunger are distinguishable from each other. This approach, however, has not been used to evaluate clinical pain syndromes. Consequently, we know little about the incidence of pain syndromes in infants, or what elements of PIV carry information about the severity of the pain or the efficacy of our attempts to manage it. We are not aware of any reviews dealing with pain in the prelingual child or PIV in animals. Because of the large number of anecdotal and uncontrolled studies, we