Opioid use and abuse is a significant social, health and economic issue in Canada. Researchers at the University of Calgary’s Faculty of Veterinary Medicine (UCVM) and Hotchkiss Brain Institute (HBI) at the Cumming School of Medicine (CSM) have discovered that an existing anti-gout medication is effective in reducing the severity of withdrawal symptoms in opioid-dependent rodents. Their work is leading to the development of a clinical trial at the Calgary Pain Clinic.
Neuroscientist Tuan Trang, PhD, and his team including PhD student Nicole Burma explored the underlying causes of opioid withdrawal and identified an important target in the spinal cord that is responsible for producing withdrawal symptoms in rats and mice. The target, called pannexin-1, is located throughout the body and importantly, in the brain and spinal cord. Using sophisticated biochemical, genetic and pharmacological techniques, they demonstrate how pannexin-1 on immune cells is producing withdrawal symptoms, and then prevent these symptoms using a drug that blocks pannexin-1 activity.
Their study was published Jan. 30 in the prestigious journal Nature Medicine and was supported by the HBI, Vi Riddell Program for Pediatric Pain, and grants from the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Rita Allen Foundation, American Pain Society, and the Canadian Foundation for Innovation.
Opioid withdrawal contributes to continued use
Opioids are a potent class of drugs used to treat pain. Stopping opioid use can result in severe withdrawal symptoms — a key contributor to continued opioid use. Currently, there are few medications that ameliorate these symptoms. For their study, Trang and Burma looked specifically at two common opioid drugs: morphine and fentanyl.
“Opioid withdrawal is aversive, debilitating and can compel individuals to continue using the drug in order to prevent these symptoms,” explains Trang, an assistant professor in the UCVM and the CSM. “In our study, we effectively alleviated withdrawal symptoms in rodents, which could have important implications for patients that may wish to decrease or stop their use of these medications.”
Prior to this study, the cellular mechanism of opioid withdrawal was not well understood, hampering the search for therapeutic avenues. Trang explains, “the focus of much of the research so far has been on neurons themselves. Our study looked at key immune cells in the nervous system — and specifically at the pannexin-1 channel on these immune cells, which is something that hasn’t been explored before.”
The discovery represents a key shift in understanding how withdrawal occurs and it opens the door to treatments that could have tremendous therapeutic potential.
Existing drug alleviates withdrawal symptoms
Once they identified the mechanism, the researchers were able to test an existing drug — in this case an anti-gout medication called probenecid that is known to have non-selective pannexin-1 blocking effects. The drug is Health Canada approved, is relatively inexpensive, and has few side-effects. Importantly, the researchers were also able to demonstrate that the drug did not affect the ability of the opioid to relieve pain.
“This is an exciting study which reveals a new mechanism and a potential therapeutic target for managing opioid withdrawal," says renowned Canadian pain researcher Dr. Michael Salter, chief of research at SickKids Hospital in Toronto. “The findings of Dr. Trang and his team could have important implications for people on opioid therapy and those attempting to stop opioid use.”
Clinical trial will test safety and efficacy in human patients
With such encouraging preclinical results, the researchers quickly started looking at how to translate this discovery to humans. They are already moving forward with Drs. Lori Montgomery and Chris Spanswick at the Calgary Pain Clinic to design a clinical trial.
“We now need to look to see if this works with patients as well as ensure safety,” says Dr. Chris Spanswick, medical leader of the Calgary Pain Program. “We are at the very early stages of organizing clinical research. It will be some time before this research gets off the ground and we look forward to continuing collaboration with the HBI on this and other areas of research.”
Opioids are the pharmacological cornerstone for treating chronic pain in a wide variety of diseases and conditions including cancer, stroke, diabetes and traumatic injury. Understanding why opioid withdrawal occurs could improve pain therapy and offer valuable support for individuals wishing to decrease their use of these drugs and also for curbing substance abuse in opioid addicts.
“This study emphasizes the importance of basic science in driving therapeutically relevant discoveries and the tremendous value of our energetic young investigators at the HBI,” says Samuel Weiss, director of the HBI. “Given the strong reliance on opiates to control pain, as well as the current opioid crisis in Canada, the potential impact for this research is immense.”
Led by the HBI, Brain and Mental Health is one of six strategic research themes guiding the University of Calgary towards its Eyes High goals.