Less morphine may be more

In mice, very low doses of morphine combined with even lower doses of a drug that usually blocks morphine’s effect can give greater pain relief than higher doses of morphine alone, according to a report in the January Brain Research.

Researchers tested pain sensitivity by measuring how long mice let their tails remain in a hot-water bath. Stanley M. Crain and his colleagues at the Albert Einstein College of Medicine in New York showed that very low doses of morphine–one-tenth to one-hundredth the normal dose–made mice more sensitive to pain than a mouse getting no morphine. These results confirmed their earlier findings showing that low doses of morphine increase the excitability of pain-related nerve cells.

When the researchers gave mice both a very low dose of morphine and an even lower dose of the morphine-blocking agent naltrexone, the mice waited longer before flicking their tails out of the hot water than when they were given the small dose of morphine alone. The effect of the combined low-dose treatment was equivalent to that of higher doses of morphine.

Low-dose morphine has both pain-triggering and pain-killing properties, Crain says. He suggests that the low-dose naltrexone blocks the morphine at nerve-cell receptors that trigger painful signals without affecting its more familiar pain-killing role.

What’s more, mice given the very low doses of morphine and naltrexone daily showed reduced pain sensitivity for several days, Crain says. Mice and people given typical doses of morphine often develop tolerance to the drug, and their pain returns.

Unpublished studies using naltrexone to boost the effect of regular doses of morphine in people “have shown very promising results,” Crain says. A tantalizing possibility, he says, is that the low-dose combination of naltrexone and morphine will work as well as full-strength morphine, yet be less likely to induce tolerance. Crain is a stockholder in a company conducting human trials of naltrexone-morphine therapy.