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Methadone-Induced Hypoglycemia

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Abstract

To determine if recent observations of hypoglycemia in patients receiving high-dose methadone extended to an animal model, we explored the effects of methadone and other mu-opioids on blood glucose levels in mice. Methadone lowered blood glucose in a dose-dependent manner with 20 mg/kg yielding a nadir in average glucose levels to 55 ± 6 mg/dL from a baseline of 172 ± 7 mg/dL, an effect that was antagonized by naloxone and mu selective antagonists β-funaltrexamine and naloxonazine. The effect was stereoselective and limited to only the l-isomer, while the d-isomer was ineffective. Despite the robust decrease in blood glucose produced by methadone, a series of other mu-opioids, including morphine, fentanyl, levorphanol, oxycodone or morphine-6β-glucuronide failed to lower blood glucose levels. Similar differences among mu-opioid agonists have been observed in other systems, suggesting the possible role of selected splice variants of the mu-opioid receptor gene Oprm1. This mouse model recapitulates our clinical observations and emphasizes the need to carefully monitor glucose levels when using high methadone doses, particularly intravenously, and the need for controlled clinical trials.

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Acknowledgments

This study was supported, in part, by Grants from the National Institute on Drug Abuse of the National Institutes of Health (DA07242, DA02615 and DA00220) to GWP and a core Grant from the National Cancer Institute of the National Institutes of Health (CA08748).

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Authors and Affiliations

  1. Department of Neurology and The Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA

    Andrew J. Faskowitz, Vladimir N. Kramskiy & Gavril W. Pasternak

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  1. Andrew J. Faskowitz
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  2. Vladimir N. Kramskiy
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  3. Gavril W. Pasternak
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Correspondence to Gavril W. Pasternak.

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Faskowitz, A.J., Kramskiy, V.N. & Pasternak, G.W. Methadone-Induced Hypoglycemia. Cell Mol Neurobiol 33, 537–542 (2013). https://doi.org/10.1007/s10571-013-9919-6

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  • DOI: https://doi.org/10.1007/s10571-013-9919-6

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