Elsevier

Biochemical Pharmacology

Volume 56, Issue 5, 1 September 1998, Pages 553-559
Biochemical Pharmacology

Commentaries
Opioid analgesics as noncompetitive N-methyl-d-aspartate (NMDA) antagonists

https://doi.org/10.1016/S0006-2952(98)00088-4Get rights and content

Abstract

Much evidence points to the involvement of N-methyl-d-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure–activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions.

Section snippets

Ketobemidone

Ketobemidone has been used in Europe for the last 50 years [32]. Based on clinical experience and clinical anecdotes, our group has tried to rationalize the clinical practice in order to select compounds suitable for the evaluation of a combination of opioid receptor agonism and noncompetitive NMDA receptor antagonism. The first compound tested was the potent opioid receptor agonist ketobemidone. Clinical anecdotes described patients with opioid-resistant pain that obtained almost complete

Methadone

Methadone, which is a synthetic μ opioid receptor agonist with an affinity for the μ receptor comparable to that of morphine [46], is used mainly for the treatment of drug addicts and, to a much lesser extent, as an analgesic. The reason for this is mainly that methadone has a highly variable biological bioavailability and a long and variable biological half-life, making it an optimal treatment for patients suffering from more complicated pain. When comparing the chemical structure of methadone

Dextropropoxyphene

Dextropropoxyphene is a weak opioid receptor agonist, which during the last 40 years has been used for the treatment of pain. The potency of dextropropoxyphene is much lower than that of morphine and codeine, reflecting a low affinity for the μ opioid receptor. Structurally, dextropropoxyphene is very similar to methadone (Fig. 1), suggesting that dextropropoxyphene may act as a non-competitive NMDA receptor agonist. In vitro studies subsequently have shown that dextropropoxyphene is a

Structure–activity relationships for morphine-like opioids

To further determine which structural characteristics are essential for the interaction of opioids with the NMDA receptor, we characterized a series of commercially available opioids with respect to their affinity for the [3H]MK-801-labelled NMDA receptor complex and in the rat cortical wedge preparation. As illustrated in Fig. 1, where the compounds are grouped according to the affinity determined in [3H]MK-801 binding, the presence of any polar group in or close to the 6 position of the ring

Conclusion

Although the finding that some opioids are weak non-competitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have evaluated the applicability of these compounds in the treatment of neuropathic pain conditions. The present knowledge about the action of these compounds with respect to NMDA receptors in vivo is so sparse that much basic research is still needed.

Acknowledgements

This work was supported by the Lundbeck Foundation. We wish to thank Dr. R. G. Hill, MSD Neuroscience Research Centre, Terlings Park, U.K., for very constructive suggestions.

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