Jan. 31, 2002 (Kingston, ON) -- A surprising discovery by researchers at Queen's University could lead to the development of more effective pain-killing drugs, with fewer side effects, for terminally ill patients or people suffering from chronic diseases such as cancer or severe pain due to nerve damage.
In a paper that appears in the February 2002 Journal of Pharmacology and Experimental Therapeutics, a Queen's team led by Dr. Khem Jhamandas of the Dept. of Pharmacology and Toxicology reports the "paradoxical" findings of their research on opioid drugs such as morphine. The usefulness of these powerful drugs can diminish dramatically after their prolonged use: a phenomenon described as drug tolerance.
Jhamandas and colleagues have found that in vanishingly small doses, opioid antagonists - normally used to block the toxic effects of opioids - instead enhance pain-killing action in experimental models. As well, they discovered that the development of tolerance to morphine was inhibited, and in cases where tolerance had already developed, it was actually reversed.
"When we received the results from the first experiment, I couldn't believe it. Everything we knew up to that point indicated that it shouldn't work - but it did!" says Jhamandas.
Combining an opiate "agonist" like morphine with its "antagonist" - in this case, the drug naltrexone - is a radical approach that was inspired by suggestions in the scientific literature that opiates have both stimulatory and depressant effects, says Jhamandas. Both types of drug act on opiate receptors which are located on nerve cells that transmit pain signals. When activated by morphine, these receptors will powerfully suppress pain.
"We decided it wasn't a question of whether a drug is agonist or antagonist, but rather a question of the dose," he explains. "In higher doses, the antagonists will very effectively destroy the effects of morphine or any other opiate drug, and traditionally they have been used to reverse toxic effects of opioids. But the paradox is that, in extremely small doses, the antagonists augment morphine's analgesic action, while reducing the development of tolerance to it. Where tolerance had already been acquired, the effectiveness of morphine was restored to between 80 and 90% of its original amount."
The latter finding is particularly significant for people with chronic illnesses who require long-term use of these drugs to control their pain. As tolerance to the drugs develops and the dose is subsequently increased, there is a greater potential for harmful side effects. As well, the manifestations of physical dependency - although not a major concern in terminal illness - can also act to increase the pain, notes Jhamandas.
The multidisciplinary Queen's research team - comprising Khem Jhamandas and graduate students Kelly J. Powell and Noura S. Abul-Husn from Pharmcology and Toxicology; and Asha Jhamandas, Mary C. Olmstead, and Richard J. Benninger from Psychology - has discovered that the interaction between morphine and antagonists occurs at specific sites in the spinal cord that transmit pain signals to the brain, and has provided quantitative measures of the observed effects. This research has been funded through the Canadian Institutes of Health Research (CIHR).
Further studies could be linked to the development of more effective pain-killing drugs that require lower dosages, have fewer side effects, and remain effective with repeated use, says Khem Jhamandas. Another area that may benefit is the treatment of neuropathic pain, which results from nerve injury, and responds poorly or not at all to opiates. If the mechanisms contributing to neuropathic pain are similar to the mechanisms contributing to the development of opiate tolerance - as is being suggested by certain studies - it is possible that ultra-low doses of antagonist drugs may help to "unplug" this resistance as well, he suggests.
The next step in this investigation will involve clinical trials to determine if the same results that have been shown in laboratory rats can be produced in people.
"This is exciting because there are so many potent chemicals in the brain that can influence pain, and we're just beginning to comprehend their functions and their promise for yielding treatments providing optimal pain relief," says Jhamandas. "In understanding how pain transmissions occur, we're learning the 'biology of pain' with the objective of making drugs that will work better."
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