Patients in pain may soon be better treated with fewer side effects using lower morphine doses combined with newer painkillers, according to a study reported by researchers from the University of California, San Francisco (UCSF), in the March 26th issue of Nature.

The research team led by Allan Basbaum, PhD, chairman of anatomy at UCSF, discovered that mild pain and more intense pain are biologically distinct and governed by different signaling molecules. In order to effectively manage intense pain, clinicians should take these distinctions into account.

"Pain is not a single phenomenon that can always be attacked with one type of analgesic drug," said Dr. Basbaum.

Two Types of Neurotransmitters

Yu Qing Cao, a graduate student working in Dr. Basbaum’s laboratory, conducted key experiments demonstrating that the neurotransmitters that signal mild pain are different from those that signal more intense pain. For several years, researchers have known that the neurotransmitter glutamate is important in signaling pain.

Mr. Cao, along with researchers in the laboratory of Charles Epstein, MD, professor of pediatrics, developed a "knockout" strain of mice lacking a gene for substance P and neurokinin A, two members of a class of neurotransmitters called the tachykinins. By measuring how long it took the mice to move away from applied mechanical pressure, or for how many seconds they licked skin after it had been dotted with pepper extract, Mr. Cao determined that the knockout mice were as sensitive to mild pain as normal mice but were much less sensitive to moderate or more intense pain.

The research team concluded that substance P, neurokinin A, or both are needed to transmit moderate or more intense pain signals. Although both the mutant and normal mice required the same amount of morphine to relieve mild pain, the mutant mice, which lacked the tachykinins, needed less morphine to relieve more intense pain.

 "Drug candidates need to be evaluated in the context of a particular pain syndrome," Dr. Basbaum said. "Pain relief often may depend on the particular medical condition and on the quality and intensity of the pain. The undertreatment of pain is a severe challenge to the quality of life of millions of seriously ailing people worldwide," added Dr. Basbaum.

"Morphine, the strongest painkiller legally prescribed in the United States, appears to act across the pain spectrum by inhibiting the pain signals transmitted by glutamate." However, Dr. Basbaum feels that morphine is not used as much as it should be because of misplaced worries about its addiction potential in pain patients.

Research Could Lead to New Analgesics to Be Combined With Morphine

 "Physicians need to better understand how to effectively administer painkillers, including morphine," he added. "But the new knowledge emerging from rodent studies about how neurokinin A, substance P, and other neurotransmitters act on different receptors could lead to drugs that provide good pain relief when used in combination with lower, less problematic doses of morphine," continued Dr. Basbaum. "This could significantly reduce the negative side effects associated with higher doses of morphine."