Drug trial cuts chronic pain’s opiates need
Australian research is paving the way for a new class of non-addictive painkillers, writes Lynnette Hoffman
IT wasn’t until after surgery abated her need for huge doses of morphine that one South Australian woman realised how much the medication she had been taking for her back pain had been disrupting her life. Her energy returned. She was no longer constantly sleepy. Her concentration improved and she could once again drive. It’s a scenario that is far from uncommon. But examples like this illustrate one of the most exasperating aspects of chronic pain — that the side effects of the drugs used to treat it can sometimes be nearly as debilitating as the pain itself, says Mark Hutchinson, a University of Adelaide post-doctoral fellow who is working with other experts in America to change that.
People often build up tolerance to the medication, requiring bigger and bigger doses to achieve the same analgesic effect, and increasing the likelihood of side effects which, in addition to those described above, can also include constipation and dry mouth.
On top of that, morphine and other opiates are highly addictive, causing cravings and creating the risk that other family members or visitors to the house not authorised to receive the drug may get hold of it.
But new research by a team of scientists from the University of Adelaide and the University of Colorado is paving the way for a new class of non-addictive drugs to treat neuropathic pain, in which the nerve fibres themselves become damaged and send incorrect signals.
Most chronic pain is neuropathic. After the original injury, such as a broken leg or a neck strain, has healed, the nerves sometimes fail to return to normal and keep sending a pain signal when there is no potentially harmful external stimuli to justify it.
University of Adelaide professor of clinical pharmacology Paul Rolan has led clinical trials to look at the effects of a drug called AV411 on patients with neuropathic pain. AV411 has been used in Asia to treat asthma for decades, but the small-scale clinical trials at the university’s Pain and Anaesthesia Research Clinic were the first to test its use for pain relief.
Patients were given AV411 along with whatever painkillers they were already taking. They were told they could reduce the dosage of other painkillers as they saw fit.
‘‘ We didn’t see a major difference in pain levels, but what we did see was a significant reduction in the doses of opioids that were required. People were needing less strong pain killers,’’ says Rolan, who presented the early findings at an international conference on neuropathic pain in Salt Lake City, Utah in November.
If lower doses can be given, it has the potential to reduce side effects and tolerance to the drug.
The breakthrough has come as a result of new research into the way morphine works.
While it’s long been known that opioids help to dull pain by acting on the neurons, the researchers found that in animal studies the drugs do something else previously unknown: they activate immune cells in the brain called glia.
‘‘ The glial cells see pain as something they have to respond to, and when you introduce morphine they see it as something foreign and become even more active. They are too eager to respond,’’ says Mark Hutchinson, who is leading the research.
The researchers identified a specific receptor that morphine uses to activate glia — and found that AV411 can block that receptor so the immune cells don’t ‘‘ see’’ the morphine.
‘‘ AV411 blocks and reverses morphine’s effects on glia, while at the same time leaving the neurons alone so the morphine can still deaden them to pain,’’ Hutchinson says.
In animals, the researchers found a link between the active glia and the ‘‘ rewarding’’ euphoric state that makes morphine pleasurable and addictive. The more rewarding a drug is, the more addictive it is.
When researchers measured the reward by monitoring the rats’ behaviour and measuring the levels of a reward chemical released from the rats’ brains, they found that there was no reward in rats that had been given morphine along with AV411. ‘‘ AV411 abolishes the reward so our rats, and hopefully people, won’t show dependence . . . if the drug is less rewarding, you’re less likely to say ‘ That was fun, let’s do it again’,’’ Hutchinson says.
As the glial cells become more active, more pain is experienced, counteracting the purpose of the drug, he says.
‘‘ So the morphine you were taking for your pain can in some cases make that pain worse,’’ Hutchinson says. ‘‘ If you had a cold virus, your immune system would be looking to attack it. In this case morphine is acting like a virus — it shouldn’t be there, and so immune cells in the brain keep getting more active to get rid of it, but they never can because you are taking it twice daily.’’
In the past when scientists have developed stronger, more powerful opioid drugs, they have also made them more rewarding. By blocking the immune cells from becoming active they could potentially combat that problem, he says.
Larger-scale clinical trials are being planned where patients will be given AV411 on its own without other pain-killing medication to see if it has an analgesic affect. More research will also be needed to see if Hutchinson’s findings around addiction and dependence hold true in humans as well.
Experts agree there is an urgent need for better drugs that target the root causes of chronic or persistent pain. Last month an MBF Foundation-funded study run by the Pain Management Research Institute at Sydney University found that 3.2 million Australians suffer from chronic pain, with an annual price tag of more than $34 billion. A third of those people are experiencing severe pain that causes substantial disability — a recent study at the PMRI found they were more disabled than people with heart failure, says PMRI director of research, professor Michael Cousins.
If indeed the results of the research do translate into a new breed of drugs it will be a welcome advance.
‘‘ Most of the drugs we have been using provide symptomatic relief for pain, but persistent pain has its own signs and symptoms and abnormalities in the nervous system. There are quite marked changes that occur in the nerves themselves in the spinal cord and brain,’’ says Cousins, who is the immediate past president of the Australian and New Zealand College of Anaesthetists (ANZCA). ‘‘ We need to be getting at disease processes with drugs that hit specific targets.’’
However, there is some way to go before we reach this goal.
‘‘ This is very interesting research but we don’t know yet how it fits in. It could be several years before this researches the clinic,’’ Cousins says. ‘‘ We need definitive information about whether this impacts on tolerance to the drug or whether it has analgesic effects of its own. We still need to tease out how big a role the glia play in addiction and tolerance compared to the nerve cells,’’ Cousins says.
Roger Goucke, dean of ANZCA’s faculty of pain medicine, also says that while it’s too early to tell what the results will ultimately be, the research seems promising.
‘‘ It’s a whole new area of pain therapy,’’ Goucke says. ‘‘ Morphine doesn’t work for all pain — and if you use it for a long time, you have to take more and more because you become tolerant to it.
‘‘ The glial cells appear to be involved in changing the message that the brain receives, so if you can use the drugs to change the way that pain is received in the brain it will be a major advance. This might be the first in a series of drugs, with better ones coming down the line.’’
Around the world pharmaceutical companies are developing drugs aimed at more than a dozen different ‘‘ targets’’ to prevent or reverse the process of persistent pain, Cousins says.
Researchers at the PRMI have also made promising discoveries — they recently identified a molecule that blocks one of the ways in which pain signals are triggered.
‘‘ Pharmaceutical companies are devoting a lot of research and money to hit these new targets and that’s good for patients,’’ Cousins says.
Pain: Researcher Paul Rolan says patients given AV411 could lower their need for opiates