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    Research Reveals New Link Between Morphine Tolerance and Increased Sensitivity to Pain

    By Jennifer Huddleston, staff writer    

    A recent study conducted by researchers at the Leiden University Medical Center in Leiden, Netherlands, and the City University of New York (CUNY) in New York City, found that a metabolite of morphine called morphine-6 glucuronide (M6G) may play a vital role in explaining the link between chronic morphine use and increased pain sensitivity.

    While this study and previous research have linked M6G to increased pain sensitivity, “we now better understand that increased sensitivity to pain caused by opioid use is not necessarily related to morphine receptors and that it may be treated by blocking other pain receptor systems in the body,” said Albert Dahan, M.D., Ph.D., lead researcher of the Leiden University Medical Center and CUNY study. “Our results could help chronic and cancer pain patients obtain a more optimized pain therapy.”
    [1]

    Dahan’s study not only involved humans, but also mice that had been bred to lack the pain receptors targeted by opioids like morphine, which helped the researchers prove that M6G operates independently of those pain receptors.

    “The incidence of increased pain sensitivity when M6G was introduced into these mice models indicates that mechanisms apart from opioid receptors play a key role in this clinical phenomenon,” said Jörn Lötsch, M.D., of the University of Frankfurt, who wrote an accompanying editorial to Dahan’s study.
    [2]

    While morphine is the drug of choice for relief of short-term, severe pain, dosages must be increased in order for the drug to remain effective. With increased dosages come increased negative side effects such as tolerance, dependency and increased sensitivity to pain.

    A previous study proved that morphine releases interleukin-1, which alerts the body to a problem by triggering sensitivity to pain in the injured area. The release of interleukin-1 heightens pain sensitivity and requires more morphine to treat the pain, thereby beginning a cycle of increased morphine dosages and increased pain. In the same study, experiments in animals revealed that combining morphine with a drug that blocks the release of interleukin-1 provided long-term pain relief without increased morphine dosages.
    [3]

    Dahan’s study showed that NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 effectively stopped the increase in pain sensitivity seen after M6G was administered. While researchers don’t have an explanation as to how NMDA receptor antagonists like MK-801 halt or reverse heightened pain sensitivity caused by prolonged use of opioids, the study’s findings do aid in the search for answers about the effects of painkilling drugs.

    The findings of the Leiden University Medical Center and CUNY study are published in the June 2009 issue of Anesthesiology.


    [1] American Society of Anesthesiologists. “Study Offers New Insights into Morphine-Induced Tolerance and Increased Pain Sensitivity.” ASA Press Release. May 21, 2009.
    [2]  Ibid.
    [3] Hebrew University of Jerusalem. “How Morphine Can Be Given More Effectively Without Having to Increase Dosages.” ScienceDaily. April 28, 2008.



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