Opioids, while undoubtedly effective, are addictive and have numerous adverse effects. Now, the discovery of a non-opioid drug’s miraculous ability to target macrophages on immune cells rather than targeting nerve cells could revolutionise our understanding of pain medicine.

The addictive potential of opioids has prompted a massive effort to find drugs capable of replacing them.

The current opioid addiction crisis in the US has prompted researchers there to find alternative strategies to treat pain. For the most part, these efforts have focused on nerve cells that transmit pain signals to the spinal cord and brain. However, new research, steered by scientists from Washington University’s School of Medicine in St Louis, indicates that targeting receptors on immune cells may be a more effective mode of treatment, especially when dealing with patients who suffer from chronic pain.

According to the study, a new non-opioid, investigational drug called EMA401 has been showing promise as a treatment for lingering nerve pain following shingles infection. In trying to understand how EMA401 helps to control pain, the Washington University research team was surprised to discover that it doesn’t target nerve cells. The drug’s target, in fact, is a receptor on immune cells.

There is a dire need for good pain-killing drugs, particularly non-opioid drugs. Generally, scientists have the understanding that targets for treating pain must be within the nervous system. However, EMA401’s target is not nerve cells, but immune cells called macrophages. The drug inhibits the angiotensin II type 2 receptor that is targeted by medications that lower blood pressure. Angiotensin is a hormone that causes blood vessels to constrict, increasing blood pressure.

This drug was thought to work by interacting with the type 2 receptor on nerve cells – the same cells that carry pain signals. But when the researchers looked more closely, they discovered that theory was wrong. When they took nerve cells from mice, put them in a culture dish and added the angiotensin hormone, nothing happened. They found that since there was no angiotensin type 2 receptor on sensory neurons, pain signals couldn’t be transmitted.

But in other experiments in which they injected the angiotensin hormone into mice, the animals indicated they felt pain and withdrew their paws when touched. When macrophages were added to the dish alongside the nerve cells, the angiotensin could ‘talk’ to the macrophages, which prompted a similar interaction between the macrophages and nerve cells, which then transmitted pain signals.

When the researchers reduced the number of macrophages in mice, the animals didn’t appear to feel pain in response to an angiotensin injection. But as the macrophages repopulated over the course of a few days, the response to pain returned. To support these observations in mice and the culture dish, the researchers also found increased numbers of macrophages alongside degenerating nerve fibres in skin biopsies taken from the legs of patients who have diabetic neuropathy.

Increasing the number of potential targets for painkillers and including targets such as receptors on immune cells may make it possible to develop more effective painkilling drugs with fewer side effects. Unlike opioids, EMA401 doesn’t cross the blood-brain barrier, thereby eliminating a number of potentially harmful side effects, including addiction and the potential for abuse. By widening the scope of potential targets to macrophages, it may be possible to develop more effective therapies for chronic, neuropathic pain.