Study offers new insights into morphine-induced tolerance and increased pain sensitivity

A study published in the June issue of Anesthesiology has shown that a drug metabolite of the opioid morphine may be a key factor in the paradoxical increased sensitivity to pain caused by chronic morphine use. For the first time, this metabolite (called morphine-6 glucuronide, or M6G) was shown to act independently of the pain receptors typically targeted during morphine administration.

The study, which was led by Albert Dahan, M.D., Ph.D., and his colleagues from the Leiden University Medical Center, Leiden, Netherlands, and the City University of New York, included both mice and human subjects and could break new ground in understanding how to treat some of the side effects of opioids and improve their analgesic properties.

“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 Dr. Dahan. “Our results could help chronic and cancer pain patients obtain a more optimized pain therapy.”

Morphine is the drug most commonly used to treat severe acute pain. After prolonged use, though, analgesic benefits become limited and it may actually increase pain sensitivity and make pain worse.

In a companion editorial to the study, Jörn Lötsch, M.D., of the University of Frankfort, explained that once morphine becomes metabolized by the body, it breaks down into two separate substances: M3G (morphine-3-glucuronide) and M6G (morphine-6-glucuronide), each playing a different role in morphine’s effects on the body.

It is M6G that Dr. Dahan’s study, and previous studies before it, has linked to unwanted increased sensitivity to pain.

One of the most critical and defining aspects of Dr. Dahan’s study, said Dr. Lötsch, is that the mice used in the research were cross-bred to be deficient in the genetic pain receptors that opioids are known to influence.

“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 Dr. Lötsch.

The $10,000 question then is this: If the pain receptors that opioids are known to target are completely blocked, what is making the subjects’ pain worse?

The answer may lie in the body’s NMDA (n-methyl-D-aspartate) receptors, which are distinctly different from opioid receptors.

Past studies have shown that anesthetics called NMDA antagonists can reverse opioid-induced sensitivity to pain. Here, again, Dr. Dahan’s results offer another new insight into morphine research.

“In our study, the NMDA receptor antagonist MK-801 was shown to be effective in blocking or reversing increased pain sensitivity after injection of the morphine metabolite M6G,” said Dr. Dahan.

There currently is no definitive explanation as to how NMDA receptor antagonists such as MK-801 can reverse the hyper-sensitivity to pain that chronic opioid use can cause.

But Dr. Dahan’s study brings researchers one step closer to solving puzzling questions about drugs that anesthesiologists and others use every day to treat pain.

“M6G may not only make an important contribution to understanding how morphine works to control pain, but also to how it causes increased sensitivity to pain,” he said. “This potential role for M6G as a factor in increased pain sensitivity in morphine use requires further study.”

For more information visit the Anesthesiology Web site at

Anesthesiologists: Physicians providing the lifeline of modern medicine. Founded in 1905, the American Society of Anesthesiologists is an educational, research and scientific association with 43,000 members organized to raise and maintain the standards of the medical practice of anesthesiology and improve the care of the patient.


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