Why Morphine Doesn’t Always Work

Morphine has long been considered the “gold standard” when it comes to pain relief. A potent and addictive painkiller derived from opium, morphine has been used for over 200 years to treat severe pain. But sometimes administering morphine can backfire – not only providing little relief, but leaving some patients hypersensitive to pain.

Scientists in Canada may have found the reason why morphine doesn’t always work.

“Our research identifies a molecular pathway by which morphine can increase pain, and suggests potential new ways to make morphine effective for more patients,” says Dr. Yves De Koninck, a professor at Université Laval in Quebec City and senior author of a study being published online in the Nature Neuroscience.

De Koninck’s research team not only identified a way to suppress morphine-induced pain, but also came to a better understanding of why some patients develop a tolerance for morphine.

“When morphine doesn’t reduce pain adequately the tendency is to increase the dosage. If a higher dosage produces pain relief, this is the classic picture of morphine tolerance, which is very well known. But sometimes increasing the morphine can, paradoxically, make the pain worse,” said co-author Dr. Michael Salter, a senior scientist and professor of physiology at University of Toronto.

“We identified specialized cells – known as microglia – in the spinal cord as the culprit behind morphine-induced pain hypersensitivity. When morphine acts on certain receptors in microglia, it triggers the cascade of events that ultimately increase, rather than decrease, activity of the pain-transmitting nerve cells.”

Researchers say a protein called KCC2 regulates the transport of chloride ions and the proper control of sensory signals to the brain. Morphine inhibits the activity of KCC2, causing hypersensitivity to pain – also known as hyperalgesia. Researchers are now testing new molecules capable of preserving KCC2 functions and thus prevent hyperalgesia.

“Our discovery could have a major impact on individuals with various types of intractable pain, such as that associated with cancer or nerve damage, who have stopped morphine or other opiate medications because of pain hypersensitivity,” says Salter.