Philip H. Heller

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.

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.

Differing correlations between pain measures in syndromes with or without explicable organic pathology

&NA; We investigated the use of pain measures in chronic pain syndromes with and without explicable organic cause by correlating scores obtained from the Visual Analog Scale and from subscales of the McGill Pain Questionnaire in patients with either inflammatory arthritis or primary fibrositis. We confirmed the finding that patients with fibrositis, despite having significantly less demonstrable pathology, report more pain on a significant number of measures. In patients with arthritis, we observed large positive correlations between scores on different pain measures, supporting the hypothesis that these scores validly measure pain secondary to tissue injury. In the fibrositis group, however, significantly lower correlations, and one even strongly negative, were found between scores on different measures. We suggest that commonly used pain measures which have been shown to be valid to study patients with demonstrable pathology may be less valid for measurement of pain in patients with syndromes such as fibrositis, whose pain may be different or more complex than that of patients with explicable organic basis.

Sexual dimorphism in very low dose nalbuphine postoperative analgesia.

In recent studies we demonstrated that the analgesic effect of the kappa-like opioids is significantly greater in women, that low dose nalbuphine (5 mg) produces profound anti-analgesia (i.e. enhances pain) in men, and that addition of a low dose of the non-selective opioid receptor antagonist naloxone (0.4 mg) to nalbuphine (5 mg) abolishes the sex difference and results in significantly enhanced analgesia in both sexes. To further delineate the dose-dependent analgesic and anti-analgesic effects of nalbuphine, the present study evaluated the effect of a lower dose of nalbuphine (2.5 mg), with and without naloxone, on dental postoperative pain. In women, nalbuphine alone induced modest, short duration analgesia, which was antagonized rather than enhanced by the addition of naloxone (0.4 mg). In men, this dose of nalbuphine alone did not produce analgesia or anti-analgesia, and naloxone (0.4 mg) did not alter the response to nalbuphine. Thus, the anti-analgesic effect of nalbuphine, present in both sexes at the 5 mg dose disappears at the lower dose of nalbuphine. In addition, the mild analgesia in women produced by this lower dose of nalbuphine is antagonized by naloxone.

Cardiovascular autonomic response during preoperative stress and postoperative pain.

Abstract Heart rate response to physiologic maneuvers was used to evaluate autonomic nervous system (ANS) function in normal control subjects and during the stress and pain experienced by patients before and after surgery. In preoperative patients (stressed without pain) and postoperative patients (stressed with pain), maneuvers which routinely increase activity in the parasympathetic or sympathetic divisions of the ANS produced only 50% of the response seen in control subjects. The heart rate response was not further reduced in patients with pain compared to patients with stress alone. The difference in heart rate response between surgical patients and control subjects was not accompanied by a difference in baseline heart rate. The data suggest that tonic stress impairs the ability of the ANS to respond fully to perturbing influences.

Enhancement of pentazocine analgesia by clonidine

&NA; Opiate‐adrenergic interactions were investigated by studying the effect of the selective alpha2‐adrenergic agonist, clonidine, on the analgesia produced by intravenous placebo and by the predominantly kappa‐opiate agonist, pentazocine, in patients with dental postoperative pain. Clonidine did not affect the pain level when administered with intravenous placebo. When administered with pentazocine, clonidine caused a statistically significant increase in pentazocine analgesia. Comparison is made to other opiate‐adrenergic interactions and possible mechanisms are discussed.

Dose ratio is important in maximizing naloxone enhancement of nalbuphine analgesia in humans.

The analgesic effect of kappa partial agonist opioids (i.e. nalbuphine, pentazocine and butorphanol) is significantly greater in women. Recent evidence suggests that this sexual dimorphism may result from a naloxone-sensitive anti-analgesic effect that is activated along with, and summates with, the analgesic effect of these agents, resulting in decreased analgesia or increased pain. For example, nalbuphine (5 mg) produces profound anti-analgesia (i.e. enhanced pain) in men, but addition of a low dose of the opioid receptor antagonist naloxone (0.4 mg, opioid antagonist) induces significant analgesia in men and enhances nalbuphine analgesia in women. To further delineate the dose-dependent relationship of nalbuphine and naloxone, we recently evaluated the effect of a lower dose of nalbuphine (2.5 mg) with and without naloxone (0.4 mg) on dental postoperative pain. In women, nalbuphine alone induced modest short duration analgesia, which was antagonized by the addition of naloxone. In men, this dose of nalbuphine alone did not produce analgesia or anti-analgesia, and naloxone did not alter the response to nalbuphine. Thus, it appeared that the 2.5 mg dose of nalbuphine was not sufficient to induce anti-analgesia while the 0.4 mg dose of naloxone was able to antagonize the analgesic effect of nalbuphine, at least in women. In the current study, we tested the hypothesis that an important determinant of naloxone enhancement of nalbuphine analgesia is the dose ratio of nalbuphine to naloxone. Since a dose ratio of 12.5:1 (i.e. 5 mg nalbuphine:0.4 mg naloxone) resulted in analgesic enhancement, but a dose ratio of 6.25:1 (2.5 mg:0.4 mg) did not, we tested the same, lower, dose of nalbuphine (2.5 mg) in combination with a lower dose of naloxone (0.2 mg) to maintain the 12.5:1 dose ratio. This lower dose of naloxone significantly prolonged the analgesic effect of nalbuphine in both men and women, suggesting that the anti-analgesic effect of nalbuphine is present in both sexes at the 2.5 mg dose and that the dose ratio of nalbuphine to naloxone is an important determinant of the analgesic efficacy of this combination.

Contribution of adrenal hormones to nicotine-induced inhibition of synovial plasma extravasation in the rat.

In this study, we examined the mechanism(s) by which s.c. nicotine inhibits synovial plasma extravasation. We found that nicotine dose‐dependently inhibited bradykinin (BK)‐ and platelet activating factor (PAF)‐induced plasma extravasation. The effect of nicotine on both BK‐ and PAF‐induced plasma extravasation was attenuated by adrenal medullectomy. ICI‐118,551 (a selective β2‐adrenoceptor blocker) (30 μg ml−1, intra‐articularly) significantly attenuated the inhibitory action of high‐dose (1 mg kg−1) nicotine on BK‐induced plasma extravasation without affecting the inhibition by low‐ (0.01 μg kg−1) dose nicotine or that on PAF‐induced plasma extravasation by nicotine at any dose. This suggested that β2‐adrenoceptors mediate the inhibitory actions of high‐dose, but not low‐dose, nicotine. We also found that systemic naloxone (an opioid receptor antagonist) (two hourly injections of 1 mg kg−1, i.p.) attenuated the inhibitory action produced by all doses of nicotine on BK‐ or PAF‐induced plasma extravasation, suggesting the contribution of endogenous opioids. RU‐38,486 (a glucocorticoid receptor antagonist) (30 mg kg−1, s.c.) and metyrapone (a glucocorticoid synthesis inhibitor) (two hourly injections of 100 mg kg−1, i.p.) both attenuated the action of high‐dose nicotine without affecting that of low‐dose nicotine. Spinal mecamylamine (a nicotinic receptor antagonist) (0.025 mg kg−1, intrathecally, i.t.) attenuated the action of high‐dose, but not low‐dose, nicotine, suggesting that part of the action of high‐dose nicotine is mediated by spinal nicotinic receptors. Combined treatment with ICI‐118,551, naloxone and RU‐38,486 attenuated the action of low‐dose nicotine by an amount similar to that produced by naloxone alone but produced significantly greater attenuation of the effect of high‐dose nicotine when compared to the action of any of the three antagonists alone.

Altered electrodermal responsivity associated with clinical pain

Abstract We used certain physiologic maneuvers to perturb the autonomic nervous system (ANS) in an attempt to detect a link between the ANS and pain. In the unperturbed state, we found no difference in the electrodermal response among normal controls, preoperative patients (increased stress without pain) and postoperative patients (increased stress and pain). The electrodermal response elicited by autonomic maneuvers was significantly attenuated in postoperative patients but not in preoperative patients or in normal control subjects.