The Search for Safer Pain Relief
A Canadian pioneer in opioid-related respiratory depression research looks to a tiny fish to solve a massive health problem
In the shadow of Canada’s COVID-19 crisis, another quiet, parallel pandemic has wreaked a different kind of havoc: opioid overdoses.
As the pandemic grew from April until December last year, there were 5,148 apparent opioid toxicity deaths in Canada— an 89 per cent increase from the same period the year before. Almost all those deaths were accidental.
Over the recent Civic Holiday weekend, there were nearly 200 calls for opioid-related overdoses. On July 30 alone, the city’s paramedic service received 51 calls for opioid-related overdoses, the most in a single day since tracking began in 2017.
Pain-killing medications like fentanyl, oxycodone or morphine can be helpful when used carefully, for short durations with a prescription and under the supervision of a physician.
But people can also become dependent on these drugs and vulnerable to overdose as their tolerance increases.
In high doses, opioids can cause people's breathing to become shallower and slower — or stop altogether.
“There’s a stigma around opioid addiction, but people from every walk of life become addicted to these drugs,” says Gaspard Montandon, a professor in the department of medicine in the University of Toronto’s Temerty Faculty of Medicine.
“And although fewer prescriptions are being issued for opioids, people who develop substance use disorders involving these medications sometimes resort to using other substances. It's a complex social problem,” says Montandon, who was among the first in Canada to study respiratory depression by opioids.
Finding a drug that delivers the same degree of pain relief without the dangerous side effects is difficult and slow work. But Montandon hopes to accelerate the process through his research.
Recently, Montandon and his team published the first research to show zebrafish can be used to identify safer alternatives to opioids. The group showed that breathing and mandible (jaw) movements in the fish changed in response to opioid painkillers.
The team also found the fish responded to pain stimuli by swimming faster and showed signs of improvement when they received pain medication. They also showed signs of withdrawal when the medication stopped.
The findings, published in the non-profit journal eLife, establish a foundation to explore new methods to identify novel pain killers.
The study also demonstrates that researchers can use zebrafish to investigate drugs to stimulate breathing, which may be useful in research into other disorders linked to breathing such as sleep apnea or respiratory problems under anesthesia.
The zebrafish genome is similar to the human genome, particularly when it comes to the mechanisms involved in opioid response. Further, zebrafish boast a complex central nervous system similar to humans.
These tiny fish, which are a type of minnow, reproduce quickly and allow scientists to test large numbers of drugs with different properties very quickly.
Montandon says testing with zebrafish can allow researchers to screen hundreds of drugs per week — a feat that would take years in other animal models.
Ordinarily, researchers screen drugs using cell cultures before moving on to other preclinical models, which can be expensive and take years to complete before testing can move into clinical trials.
“My lab is in a building close to a safe injection site, and I see people being taken to hospital,” says Montandon, who is also the interim director of the Drug Discovery & Zebrafish Facility at the Keenan Research Centre for Biomedical Research in St. Michael’s Hospital, Unity Health Toronto. “I wanted my research to be faster. I didn’t want to wait 10 or 15 years or even a whole career to find a solution.”
Right now, Montandon’s lab is exploring whether a combination of opioids and drugs called respiratory stimulants can provide pain relief without negatively affecting breathing.
The team is also investigating whether they can target a different mechanism to boost the respiratory system with the goal of providing pain relief without slowed breathing.
The research was supported by the St. Michael’s Hospital Foundation and the JP Bickell Foundation, as well as the Canadian Institutes of Health Research.