Gear Robert W, Gordon Newton C, Miaskowski Christine, Paul Steven M, Heller Philip H, Levine Jon D
Department of Oral and Maxillofacial Surgery, University of California, San Francisco, CA 94143, USA.
Neurosci Lett. 2003 Nov 6;351(1):5-8. doi: 10.1016/s0304-3940(03)00939-x.
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.
κ 部分激动剂阿片类药物（即纳布啡、喷他佐辛和布托啡诺）对女性的镇痛效果显著更强。最近的证据表明，这种性别差异可能是由一种对纳洛酮敏感的抗镇痛作用引起的，该作用与这些药物的镇痛作用同时被激活并与其相加，导致镇痛作用减弱或疼痛加剧。例如，纳布啡（5毫克）在男性中产生显著的抗镇痛作用（即疼痛增强），但添加低剂量的阿片受体拮抗剂纳洛酮（0.4毫克，阿片拮抗剂）可在男性中诱导显著的镇痛作用，并增强女性的纳布啡镇痛效果。为了进一步阐明纳布啡和纳洛酮的剂量依赖关系，我们最近评估了较低剂量的纳布啡（2.5毫克）在有或没有纳洛酮（0.4毫克）的情况下对牙科术后疼痛的影响。在女性中，单独使用纳布啡诱导适度的短期镇痛，添加纳洛酮可拮抗这种镇痛作用。在男性中，该剂量的纳布啡单独使用既不产生镇痛作用也不产生抗镇痛作用，纳洛酮也不改变对纳布啡的反应。因此，似乎2.5毫克剂量的纳布啡不足以诱导抗镇痛作用，而0.4毫克剂量的纳洛酮能够拮抗纳布啡的镇痛作用，至少在女性中是这样。在本研究中，我们检验了这样一个假设，即纳洛酮增强纳布啡镇痛作用的一个重要决定因素是纳布啡与纳洛酮的剂量比。由于12.5:1的剂量比（即5毫克纳布啡:0.4毫克纳洛酮）导致镇痛作用增强，但6.25:1的剂量比（2.5毫克:0.4毫克）则不然，我们测试了相同的较低剂量的纳布啡（2.5毫克）与较低剂量的纳洛酮（0.2毫克）联合使用，以维持12.5:1的剂量比。这种较低剂量的纳洛酮在男性和女性中均显著延长了纳布啡的镇痛作用，表明2.5毫克剂量的纳布啡在两性中均存在抗镇痛作用，且纳布啡与纳洛酮的剂量比是该联合用药镇痛效果的一个重要决定因素。
