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The agonist-antagonist kappa-opioid nalbuphine administered for postoperative pain produces greater analgesia in females than in males. In fact, males administered nalbuphine (5 mg) experience pain greater than those receiving placebo, suggesting the existence of an anti-analgesic effect. These sexually dimorphic effects on postoperative pain can be eliminated by co-administration of a fixed ratio of the prototypical opioid receptor antagonist naloxone with nalbuphine, implying a role for opioid receptors in the anti-analgesic as well as analgesic effects of nalbuphine. In the present study, we further evaluated the role of opioid receptors in the sex-specific effects on pain produced by nalbuphine by co-administering a dose of morphine low enough that it does not produce analgesia. Following extraction of bony impacted third molar teeth, nalbuphine (5 mg) was administered alone or in combination with either of two low doses of morphine (2 mg or 4 mg). Both doses of morphine reversed nalbuphine-induced anti-analgesia in males, but only the lower dose (2 mg) reached statistical significance. Neither dose affected nalbuphine-induced analgesia in females, and when administered alone in either males or females, morphine (2 mg) had no analgesic effect. Though not observed in females, the effect of morphine in males argues that, like naloxone, low dose morphine may act as an anti-analgesia opioid receptor antagonist.
Previously we reported that the nalbuphine produces both analgesic and anti-analgesic effects, and that the opioid antagonist naloxone can enhance nalbuphine analgesia by selectively antagonizing the anti-analgesic effect. Here we show that morphine, given in a subanalgesic dose, reverses nalbuphine-induced anti-analgesia in males, perhaps by a similar mechanism.
The agonist-antagonist kappa (κ)-opioids—nalbuphine, pentazocine, and butorphanol—produce greater postoperative analgesia in females than in males6,9,12. We have proposed that this sexually dimorphic effect results from the ability of κ-opioids to produce anti-analgesia as well as analgesia. In a placebo-controlled study of postoperative pain, we observed that males receiving nalbuphine (5 mg) actually experienced greater pain than those receiving placebo10. In subsequent studies, co-administration of a low dose of the opioid antagonist naloxone was shown to enhance nalbuphine analgesia in both females and males, and eliminate this sexual dimorphism7,8,11, suggesting that anti-analgesia induced by nalbuphine is sensitive to naloxone and is present in both females and males, though more so in males. We proposed that nalbuphine produces two opposing effects, “analgesia” and “anti-analgesia,” by acting at distinct opioid receptors, and that anti-analgesia is more sensitive to naloxone antagonism than is analgesia 11. To further test the possibility that nalbuphine produces anti-analgesia by action at an opioid receptor, we investigated the effect of subanalgesic doses of morphine, an opioid that binds to µ-, κ-, and δ-opioid receptors19, on nalbuphine analgesia.
In this study, 116 patients underwent surgery for removal of third molar teeth, including at least one bony impacted mandibular third molar (see Table 1 for group characteristics). The surgical protocol includes intravenously administered diazepam, nitrous oxide and oxygen administered by inhalation, and local anesthetic injection (mepivacaine without vasoconstrictor to obtain a nerve block of shorter duration) 6,13,14. Following surgery, groups of males and females received nalbuphine (5 mg) alone, morphine (2 mg) alone or nalbuphine (5 mg) combined with either of two doses of morphine (2 mg or 4 mg). This double-blind, randomized study, in which all patients were studied in an interspersed fashion, conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Committee on Human Research at the University of California, San Francisco. Written informed consent was obtained from each research subject.
Pain intensity was quantified by asking patients to place a mark on a 10 cm visual analog scale (VAS), which was anchored on the left side with the words “No Pain” and on the right with the words “Worst Pain Imaginable.” Pain ratings were obtained at 20 minute intervals beginning 50 minutes after the onset of local anesthesia (i.e., the beginning of the surgical procedure). The study drug(s) was administered through an indwelling intravenous line 10 minutes after the “baseline” VAS pain rating, which was defined as the first VAS pain rating ≥3 cm occurring at least 70 minutes after the start of surgery. The duration of the experiment, measured from the time of study drug administration, was three hours.
Differences in demographic characteristics among the treatment groups were determined using separate one-way analyses of variance (ANOVAs) for each sex. The between-subjects factor for each of these ANOVAs was treatment with four levels.
Analgesic response was defined as the difference (cm) between the VAS pain rating at each time point following study drug administration and the baseline VAS pain rating just prior to drug administration. Differences in analgesic responses among the treatment groups were determined using separate two-way repeated measures ANOVAs for each sex with one within-subjects factor (time with 9 levels) and one between subjects factor (treatment with four levels). For each ANOVA, the Mauchly criterion was used to determine if the assumption of sphericity for the within-subjects effects was met. If the Mauchly criterion was not satisfied, Greenhouse-Geisser adjusted p values are presented. If significant treatment group × time interaction occurred, the simple main effects were examined over time to help explain the significant interaction.
One-way ANOVAs for males showed a significant difference among the four treatment groups in only the age variable (p=0.037). However, none of the six possible pairwise contrasts showed significant differences using the Scheffé criterion. Also, since age is not significantly related to pain score, it was not used as a covariate in the subsequent repeated measures ANOVA analysis.
The response of males who received nalbuphine (5 mg) or morphine (2 mg) alone, or nalbuphine combined with morphine (2 mg or 4 mg) are depicted in Figure 1. Two-way, repeated measures ANOVA demonstrated a significant main effect of treatment (F(3,52)=4.364; p = 0.008) as well as time (F(8,416) = 10.460; p < 0.001). The treatment by time interaction was not significant. Post hoc analysis (Scheffé) revealed that on average the nalbuphine alone group was significantly different from the nalbuphine plus morphine (2 mg) group (p=0.014) but not significantly different from the nalbuphine plus morphine (4 mg) group (p=0.079), the group that received only morphine was not significantly different from any of the other groups.
One-way ANOVAs for females showed a significant difference among the four treatment groups in only the baseline VAS pain variable (p = 0.007). Post hoc pairwise contrasts using the Scheffé criterion indicated that baseline VAS pain was approximately 1.7 centimeters higher in the group that received nalbuphine (5 mg) combined with morphine (4 mg) than the group that received nalbuphine alone. Consequently, baseline VAS pain was included as a covariate in the subsequent repeated measures ANOVA analysis.
The responses of females who received nalbuphine (5 mg) or morphine (2 mg) alone, or nalbuphine combined with morphine (2 mg or 4 mg) are depicted in Figure 1. Two-way, repeated measures ANOVA did not demonstrate either significant main effects of time or treatment or a time × treatment interaction.
In a previous study that did not examine for sex differences we reported that morphine (2 mg) enhanced the analgesic effect of the agonist-antagonist κ-opioid pentazocine 14. In the present study, we found that morphine reversed the anti-analgesic effect of nalbuphine, but that this effect was statistically significant only in males. Neither dose of morphine produced a significant effect in females.
The effect of morphine on the ability of nalbuphine to produce analgesia could be due to the summation of separate analgesic effects of morphine acting at µ-opioid receptors and nalbuphine at κ-receptors, but examination of the data does not support this explanation in the current study. While, an additive effect of morphine might be expected to be similar in both sexes, this was not the case; the effect of morphine was significant only in males. Also, with analgesic summation the higher (4 mg) dose of morphine should have produced greater enhancement than the lower (2 mg) dose, but if anything the opposite was observed. In combination with nalbuphine only the 2 mg morphine dose significantly improved the analgesic effect of nalbuphine alone in males.
An alternative explanation—one that is more consistent with the current findings—is that nalbuphine analgesia is unmasked by morphine blockade of the action of nalbuphine at an anti-analgesia receptor. Previously, we showed that the opioid receptor antagonist naloxone enhances nalbuphine analgesia in both sexes (males > females)11, a finding that formed the basis of a two-receptor hypothesis for the effect of nalbuphine on postoperative pain 5,7,8,11. According to this hypothesis, nalbuphine induces anti-analgesia as well as analgesia by acting at distinct “anti-analgesia” and “analgesia” opioid receptors. Thus, the effect of nalbuphine alone on pain is observed as the sum of these two opposing actions. To account for the sexually dimorphic analgesic effect of κ-opioids, the hypothesis proposes that males have more “anti-analgesia” receptors than females. The ability of naloxone to enhance κ-opioid analgesia and eliminate the sexual dimorphism results from naloxone’s greater affinity for the anti-analgesia receptor.
While nalbuphine, morphine, and naloxone all bind to µ-, δ-, and κ-opioid receptors 3,18, the efficacy of each drug as an agonist is markedly different. Naloxone, the prototypical opioid receptor antagonist is essentially devoid of agonist efficacy at any opioid receptor15. The efficacy of nalbuphine is relatively low at the µ-opioid receptor, which is consistent with its ability to antagonize some actions of morphine 2,21 and still act as a low efficacy µ-agonist, for example in producing mild respiratory depression, when administered alone20. In contrast, morphine is well known as a highly efficacious µ- opioid receptor agonist with little if any efficacy at κ-opioid receptors 16,17.
If the anti-analgesia receptor is an opioid subtype, morphine, like naloxone, appears to function as an antagonist at this receptor blocking the anti-analgesic effect of nalbuphine. However, since higher doses of morphine produce analgesia, the analgesic effect of a combination of any given pair of µ and κ opioid agonists likely depends on an array of factors, including the dose ratio of the two drugs, and their relative binding affinities for the relevant opioid receptor subtype. Different dose ratios could result in enhanced analgesia, diminished analgesia, or no change in analgesia compared to either drug alone 1,14,22. In addition, the relatively short plasma half-lives of both morphine and naloxone imply that plasma concentrations of these drugs do not correspond well with the prolonged time course of analgesia. Future studies to address the optimal dose ratio for morphine to enhance nalbuphine analgesia in both males and females should provide useful information with respect to properties of the receptor at which drugs such as morphine and naloxone act to block nalbuphine-induced anti-analgesia.
In summary, doses of morphine well below the lowest dose that produces analgesia reversed nalbuphine-induced anti-analgesia in both females and males with postoperative pain. Further investigation is needed to determine the optimal dose ratio that provides maximum enhancement of nalbuphine analgesia in males and females. Identification of the receptor(s) at which agonist-antagonist κ-opioids act to induce anti-analgesia is important in order to understand the mechanism(s) underlying sexual dimorphism in opioid analgesia and might aid in the development of novel analgesic drugs selectively targeted at the analgesia receptors and/or antagonists selectively targeted at anti-analgesia receptors. Eliminating agonist-antagonist κ-opioid-induced anti-analgesia would not only produce greater analgesia using lower doses of opioids, but potentially also decrease side effects, including abuse liability.
We thank Gretchen Summer, R.N., Ph.D., for excellent technical assistance. This work was supported by National Institutes of Health (DE018526).
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