Animal Studies Show Promise for Safer Opioids

By Pat Anson, Editor

Animal studies currently underway could hold the key to developing new opioid therapies that relieve pain without the risk of addiction, overdose and other harmful side effects.

Researchers at Wake Forest Baptist Medical Center in North Carolina have developed a pain killing compound -- called BU08028 – that relieves pain in monkeys without causing physical dependence. BU08028 is similar to buprenorphine, an opioid currently used to treat both pain and addiction.

"Based on our research, this compound has almost zero abuse potential and provides safe and effective pain relief," said Mei-Chuan Ko, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist and lead author of the study published in the Proceedings of the National Academy of Sciences.

"This is a breakthrough for opioid medicinal chemistry that we hope in the future will translate into new and safer, non-addictive pain medications."

This study, which was conducted on 12 monkeys, targeted a combination of mu opioid receptors in the brain – the same receptors targeted in humans by existing opioid pain medication.

The Wake Forest researchers examined behavioral, physiological and pharmacologic factors and found that BU08028 blocked pain signals without the side effects of respiratory depression, itching or adverse cardiovascular events. In addition, the study showed pain relief lasted up to 30 hours in the monkeys and repeated administration did not appear to cause physical dependence.

"To our knowledge, this is the only opioid-related analgesic with such a long duration of action in non-human primates," said Ko. “Given the decades-long effort aimed at developing abuse-free opioid analgesics, BU08028 represents a major breakthrough for opioid medicinal chemistry.”

Ko plans further animal studies on related compounds to see if they have the same safety profiles as BU08028. If those studies are successful, he hopes to begin studies on humans with the ultimate goal of getting FDA approval for a new class of opioid medication.

The research is funded by the National Institutes of Health and National Institute on Drug Abuse.

Rat Study Targets Peripheral Nerves

Another animal study is taking a different approach to pain relief – by targeting nerves in peripheral tissue – not the mu opioid receptors in the brain and spinal cord.

In findings published in Cell Reports, researchers at the University of Texas found that targeting delta opioid receptors on sensory neurons in the peripheral tissue of laboratory rats produces fewer side effects and with much lower abuse potential.

"Being able to increase the responsiveness of peripheral opioid receptor systems could lead to a reduction in systemic opioid administration, thereby reducing the incidence of side effects," says senior study author Nathaniel Jeske of the University of Texas Health Science Center at San Antonio.

One complication is that delta opioid receptors in peripheral tissues only become activated in the presence of inflammation. Because it has not been clear how to overcome this need for an inflammation trigger, the development of drugs that target peripheral nerves has been limited.

Jeske and his colleagues discovered a protein called GRK2 that binds to and prevents delta opioid receptors on rat sensory neurons from responding normally to opioids. But when those peripheral nerves were exposed to a natural inflammatory molecule called bradykinin, GRK2 moved away from the delta opioid receptors, setting off a biochemical reaction that restored the functioning of these receptors.

In addition, rats with reduced GRK2 levels in peripheral sensory neurons regained sensitivity to the pain-relieving effects of a drug that activates delta opioid receptors, and without the need for an inflammatory trigger.

The researchers hope to replicate the same findings using human tissues.

"By shedding light on how inflammation activates delta opioid receptors, this research could potentially lead to the development of safer, more effective opioids for the treatment of pain," said Jeske, whose work is funded by the National Institutes of Health.

Researchers Say Chronic Pain Changes Brain Chemistry

By Pat Anson, Editor

A new study by UK researchers raises an intriguing question: Does chronic pain change brain chemistry and make pain more tolerable?

The answer is yes, according to a small study at the University of Manchester. Researchers there used Positron Emission Tomography imaging (PET scans) to measure the spread of opioid receptors in the brains of 17 arthritis sufferers and nine healthy control subjects

When they applied heat to the skin of study participants to induce pain, researchers found that the more opioid receptors they had, the higher their ability was to withstand pain. The number of opioid receptors was highest in arthritis sufferers, suggesting their brain chemistry had changed in response to chronic pain.

"As far as we are aware, this is the first time that these changes have been associated with increased resilience to pain and shown to be adaptive,” said Dr. Christopher Brown. "Although the mechanisms of these adaptive changes are unknown, if we can understand how we can enhance them, we may find ways of naturally increasing resilience to pain without the side effects associated with many pain killing drugs."

image courtesy of university of manchester

It’s been known for a long time that we have receptors in our brains that respond to natural endogenous opioids such as endorphins. Those same receptors also respond to opioid pain medications.

Some people seem to cope better with pain than others, and knowing more about their resilience and coping mechanisms may lead to the development of new ways of treating pain.

"This is very exciting because it changes the way we think about chronic pain,” said Anthony Jones, a professor and director of the Manchester Pain Consortium. "There is generally a rather negative and fatalistic view of chronic pain. This study shows that although the group as a whole are more physiologically vulnerable, the whole pain system is very flexible and that individuals can adaptively upregulate their resilience to pain.

"It may be that some simple interventions can further enhance this natural process, and designing smart molecules or simple non-drug interventions to do a similar thing is potentially attractive."

Researchers at Stanford University in California have also been studying this subject, trying to learn why some chronic pain sufferers are more resilient to pain.

“I think this study emphasizes some very important points about pain resilience,” said Dr. Drew Sturgeon, a fellow in the Stanford University Pain Management Center and Stanford Systems Neuroscience and Pain Laboratory. “If you think about chronic pain as something that poses a constant challenge and requires frequent adaptation, it makes sense that we would see changes in the brain that correspond with this process.  We see it frequently from a psychological standpoint, where people are able to learn and develop better strategies for coping with pain and reduce their fear and negative thoughts about pain after dealing with it for a while.”

Sturgeon and his colleagues say resilience may also stem from an enhanced ability to enjoy the rewarding parts of life – which makes it easier to cope with pain.  

“The idea would be that if a person had more opioid receptors available they would be more sensitive to the good stuff in life, and therefore more motivated by pleasurable experiences, such as spending time with friends, exercising -- rewards that get us back on the road to living a meaningful life,” said Beth Darnall, PhD, a pain psychologist, clinical associate professor at Stanford University and author of Less Pain, Fewer Pills.

“Theoretically, people who are known to be resilient probably have more endogenous opioids -- or they have made choices in life to optimize their experience of endogenous opioids and therefore have honed an internal reward system.”

Whatever the cause of resilience, many patients hope further studies will uncover new ways of treating pain.

"As a patient who suffers chronic pain from osteoarthritis, I am extremely interested in this research. I feel I have developed coping mechanisms to deal with my pain over the years, yet still have to take opioid medication to relieve my symptoms,” said Val Derbyshire. “The notion of enhancing the natural opiates in the brain, such as endorphins, as a response to pain, seems to me to be infinitely preferable to long term medication with opiate drugs.”

The University of Manchester study is being published in Pain, the official journal of the International Association of the Study of Pain.