Elsevier

Neuroscience Letters

Volume 351, Issue 1, 6 November 2003, Pages 5-8
Neuroscience Letters

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

https://doi.org/10.1016/S0304-3940(03)00939-XGet rights and content

Abstract

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.

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Acknowledgements

We thank Gretchen Summer, R.N., for excellent technical assistance. This work was supported by NIH grant NR03923 and the Kaiser Community Services Program.

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    Furthermore, nalbuphine co-administered with naloxone at the same fixed dose ratio that was maximally effective in patients (12.5:1) blocked anti-analgesia without affecting analgesia, whereas a slightly higher dose of naloxone (dose ratio: 12.5:2) also reversed analgesia, again closely replicating our findings in patients with postoperative pain (Gear et al., 2000). To explain our clinical findings, we proposed that the receptor at which an agonist–antagonist acts to produce analgesia (Gutstein and Akil, 2001) is different from the receptor at which it acts to produce anti-analgesia (Gear et al., 2000; Gear et al., 2003; Kshirsagar et al., 2008). This suggestion is supported by our current observation that the selective κ-receptor agonist U69593 only induces analgesia, and confirmed by the failure of the selective kappa antagonist nor-BNI to block nalbuphine-induced anti-analgesia.

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