New questions about old Canadian study foreshadowing opioid crisis

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More than 20 years ago, a team of Vancouver doctors discovered disturbing signs of a future opioid crisis —  research that was noticed at the time by U.S. officials from Purdue Pharma, the company that made OxyContin, according to a report this week in the New York Times (NYT).

It raises new questions about how long the pharmaceutical industry knew their opioid pain pills were being abused and whether early warnings were ignored.

It also raises questions about what Canadian regulators knew about the addiction risk of the new opioid drugs and whether Health Canada could have acted to avoid the crisis that has killed thousands of Canadians over the last two decades.

Back in 1997, Dr. Stefan Grzybowski was getting repeated requests for large quantities of prescription narcotics at his downtown Vancouver medical clinic.

"I remember one fellow telling me that if I didn't give him the pills he'd just have to go buy them on the street," he told CBC News.

That prompted Grzybowski, who is also a research professor at UBC, to investigate the illegal dealing of prescriptions drugs. He began by asking his patients for information about which drugs were selling on the street and how much they cost. But he wasn't getting very far. Then his colleague, Dr. Amin Sajan, a medical resident, tried a different approach.

"He [went] right downtown and interviewed the buyers and sellers on the steps of the Carnegie Centre, which was quite a brave and amazing thing to do."

What they discovered shocked them. They found that lots of prescription sedatives and narcotic drugs were selling on the street at surprisingly high prices. And the most valuable drugs were morphine MS Contin pills made by Purdue Pharma — called "peelers" because the coating on the pill was peeled back to release the drug inside.

This was one of the first formal studies on the street value of prescription drugs. When the findings were published in the CMAJ in July, 1998 the research came to the attention of Purdue Pharma officials, according to the NYT story.

Aggressive marketing campaign

The opioid manufacturer was running an aggressive marketing campaign to promote its new opioid, OxyContin, a synthetic oxycodone-based pain medication — stronger than morphine — approved a few years earlier.

"Purdue Pharma, the company that planted the seeds of the opioid epidemic through its aggressive marketing of OxyContin, has long claimed it was unaware of the powerful opioid painkiller's growing abuse until years after it went on the market," NYT reporter Barry Meier wrote.

"But a copy of a confidential Justice Department report shows that federal prosecutors investigating the company found that Purdue Pharma knew about "significant" abuse of OxyContin in the first years after the drug's introduction in 1996 and concealed that information."

CBC News has not seen the documents and has not been able to independently verify the NYT story.

In a document of 'supporting facts' sent to Health Canada, Dr. Persaud's group included an image of a Purdue Pharma advertisement to Canadian doctors in 2000 from the journal Canadian Family Physician. (Submitted by Dr. Nav Persaud)

Among the evidence in Justice Department documents cited by the NYT are references to the Canadian study. The NYT story quoted a Purdue Pharma spokesperson who said, "The company did not consider the small study's results significant because it was already known that morphine could be abused."

But back in 1998, in the same CMAJ issue, Dr. Brian Goldman wrote an editorial saying the Vancouver study should "ring alarm bells."

"The relatively high street price of controlled-release opioid analgesics reported in this study clearly indicates that these drugs are coveted," Goldman wrote, adding a prescient warning about the new opioids.

"Now that controlled-release oxycodone has been licensed in Canada, we can expect that it and other controlled-release opioid analgesics will also find their way onto the black market."

Today Goldman, an emergency physician, is host of CBC Radio's White Coat, Black Art. Back then he was studying opioid abuse and was also a paid speaker for Purdue Pharma, which was marketing its new long-acting opioid OxyContin to Canadian doctors.

(Goldman has written about his experience with the pharmaceutical industry.)

Goldman said the CMAJ asked him to write the commentary and his work with Purdue Pharma had no influence over what he wrote.

"I never heard a word from Purdue. I have no idea how they reacted to it."

He said it was obvious at the time that opioids had the potential to become a problem. But he didn't know just how big the problem would ultimately become.

"I certainly wish I had a hint of what was to come, back then."

The CMAJ articles were among the first in a series of unheeded warnings about the unfolding disaster caused by prescription pain pills on both sides of the border.

Small print at the bottom of the ad states 'Drug abuse is not a problem in patients with pain for whom the opioid is appropriately indicated.' (Submitted by Dr. Nav Persaud)

"Obviously it's also evidence that the risks were known in Canada," said Dr. Nav Persaud, one of a group of Canadian academics calling for a criminal investigation into the marketing of opioid drugs in Canada.

In 2004 the Newfoundland and Labrador government was so alarmed by opioid deaths that it established an OxyContin task force which found that "the bulk of OxyContin on the streets originates with prescriptions generated in the province."

The task force called on Ottawa to take a closer look at the marketing of opioids in Canada "to ensure that pharmaceutical manufacturers use appropriate marketing strategies that includes information on the dangers of drug abuse and diversion."

"Obviously Health Canada should have looked into the issue then, and if they had looked into it properly in 2004 we might not have the magnitude of the crisis that we do have today," Persaud said.

In 2009, the CMAJ published another study showing that opioid-related deaths in Ontario doubled after the introduction and marketing of long-acting opioid drugs.  

And in 2011, an Ontario coroner's jury investigating the opioid-related deaths of two people in Brockville issued 48 recommendations related to the treatment and prescribing of prescription opioids.

Opioid crisis lands in U.S. court

Back in the U.S., the opioid crisis had landed in court. In 2007, three top company officials pleaded guilty to criminal charges that their marketing campaign was misleading. In the statement of facts from the court proceedings the officials agreed that its sales people told some doctors that OxyContin "had less addiction potential, had less abuse potential, was less likely to be diverted than immediate-release opioids."

At this point hundreds of local governments in the U.S. and more than 20 states have taken legal action against drug makers over the opioid crisis.

In Canada, a class action suit was launched by a group of patients against Purdue Pharma. The two sides agreed to a $ 20 million settlement, but the process is on hold after a Saskatchewan judge rejected the settlement, saying he wasn't convinced it was fair. As part of the agreement, the settlement between the company and the victims must be approved by courts in Ontario, Nova Scotia, Quebec and Saskatchewan.

"In Canada there's apparently been no criminal investigation at all," Persaud said. That's why he and a group of doctors and professors are demanding that the attorney general and Health Canada take action.

In a document of "supporting facts" sent to Health Canada, Persaud's group included an image of a Purdue Pharma advertisement to Canadian doctors in 2000 from the journal Canadian Family Physician. In small print the ad states "Drug abuse is not a problem in patients with pain for whom the opioid is appropriately indicated."

But research has since shown that there is a risk of opioid addiction even when using the medication as prescribed by doctors.

Obviously Health Canada should have looked into the issue then, and if they had looked into it properly in 2004 we might not have the magnitude of the crisis that we do have today.— Dr. Nav Persaud

Based on the NYT revelations about the Canadian study, Persaud and his colleagues sent a third request for a criminal investigation to the federal government on Friday.

And Persaud wants to know if Health Canada also saw the 1998 study.

"Have they seen this report or did they just read about it in the New York Times?" Persaud asked.

Health Canada's spokesperson, Rebecca Purdy, said in an email, "Given that this study is 20 years old, it is not possible at this time to ascertain whether or not individuals within Health Canada were aware of the specific study in 1998."

Did Purdue Pharma officials in Canada see the 1998 Vancouver study? They did not answer the question directly, but the company's senior director, government and stakeholder affairs, Walter Robinson, wrote in an email, "Purdue Pharma (Canada) continuously monitors the environment for third-party publications in peer-reviewed journals that relate to our products and the therapeutic areas in which we operate."

"Purdue Pharma (Canada) has always marketed its products in line with the Health Canada approved product monograph and in compliance with all relevant rules, regulations and codes," Robinson wrote, adding that Purdue Pharma (Canada) and Purdue Pharma L.P.  (USA) are associated companies, but are operated independently.

'A serious and growing opioid crisis'

A 2017 federal report on opioid-related deaths stated that "Canada is experiencing a serious and growing opioid crisis," that claimed up to 4,000 lives last year alone. The Public Health Agency of Canada said  "illegally produced fentanyl and other synthetic opioids remain a growing driver of this crisis."

Back at UBC, Grzybowski is now research director in the department of family practice, and he's studying how to provide rural health services to vulnerable populations.  

Looking back on that 1998 paper, he said it seemed the observations about the growing appeal of prescription pharmaceuticals were ignored.

"In terms of any health policy changes or any particular pharmaceutical manufacturing changes, I don't think a lot happened in response to the paper," he said. "Obviously it should have."

"We were definitely surprised by what we learned and we did flag it, but it's the standard problem of the academic literature that you think you've found something important you publish it and then nothing really happens."

"I feel vindicated to some degree that we found something important and people are appreciating it now."


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