The British Columbia Coroners Service Death Review Panel’s report on drug overdose deaths, released last month, was grim and to the point. “The clearest finding that has come through this review is the reaffirmation that the biggest problem we face in terms of overdose deaths is the recent increase in drug toxicity,” stated Michael Egilson, head of the coroner service’s child and death review unit.

Comprising 21 experts from the health care, policing, education, mental health and addictions sectors as well as First Nations, the panel examined all overdoses from illicit drugs reported in BC between January 2016 and July 2017. In 2016, 931 British Columbians died from illicit drug overdoses and the following year that number rose to 1,156. Statistics for 2018 are not yet available, but by February the province was averaging 3.6 overdoses a day, which could again raise the annual total.

 Canadian Institute for Health Information

CIHI statistics. Credit: Canadian Institute for Health Information

In order to put BC’s problem in perspective, consider that the entire country saw 4,000 overdose deaths from the beginning of 2016 to the middle of 2017, so that about a third of the total was in this single region. Egilson pointed to the “potency and content of illicit substances” as a cause; among the most notorious of those substances is the synthetic psychoactive opioid fentanyl and its estimated 50-plus analogs, which are sometimes called “fentalogs” or “bootleg” fentanyl. These are being cut into heroin, cocaine, methamphetamine and other products, including the deadly carfentanil, which is 100 times more potent than fentanyl and considered a possible chemical weapon by United States authorities.

According to the BC Coroners Service, in 2012 fentanyl was linked to just four percent of overdose deaths, but by 2015 that figure had risen to 29 percent, only to rise over the next year to 67 percent and then again to 81 percent last year.

For the Death Review Panel these numbers pointed to a need for access to safer drugs, a conclusion that included a call for “tools like drug checking.”

For some Canadian chemists, the task of analyzing drugs has become a major priority, especially for those whose work embraces mass spectrometry (MS). Since an amount of carfentanil the size of a grain of sand is enough to kill you, these chemists find themselves on the front lines of Canada’s opioid crisis, wielding a scientific tool that enables them to pinpoint minute traces of fentalogs in drug samples.

Science hits the street

One such researcher is McMaster University Department of Chemistry and Chemical Biology professor Philip Britz-McKibbin. His ongoing work in metabolomics has focused on metabolite profiling in complex human biofluids, a key area for advances in drug screening. One of his lab’s specialty techniques is a patented high-throughput method, multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS), which is more accurate than the current immunoassay urine testing regime that can overlook a wide range of synthetic opioids, stimulants, and tranquilizers. This fundamental innovation introduces multiplexed separation prior to high-resolution time-of-flight mass spectrometry.

 JD Howell

Professor Philip Britz-McKibbin, of McMaster University Department of Chemistry and Chemical Biology. Photo credit: JD Howell 

“We’ve developed a unique separation method to greatly improve sample throughput and data fidelity,” Britz-McKibbin explains, “because that’s really a major bottleneck in comprehensive drug screening when using mass spectrometry.”

Removing this bottleneck means that results from urine samples, typically obtained with liquid chromatography-MS, can be turned around much faster —in as little as two to three minutes. As fast as this is, it remains a laboratory method unsuited to an emergency situation, such as dealing with an overdose in progress. Rather than serving first responders, MSI-CE-MS bridges the gap between first- and second-tier testing; it could potentially replace immunoassays to bring expanded, cost-effective screening to a potentially unlimited number of drugs and their metabolites, thereby reducing the occurrence of false-positive and false-negative results.

These misleading immunoassays usually emerge from cross reactivity, when antibodies binding to similar small molecules are found in urine. Such limitations could compromise patients as they are being tested for drug substitution or medication compliance along with the presence of drugs of abuse (as the most prominent recreational agents are known). Nor can immunoassays always identify a unique drug; instead they can only confirm the broader drug class, which could include anything from an illicit street opioid analog to a legal prescription.

Britz-McKibbin notes that the new method provides sufficient chemical information to prove that the substance is a specific compound, rather than simply a member of a given class. And it can go even further, fragmenting the molecule to provide a characteristic MS spectrum or unique chemical fingerprint.

“This gives you almost three dimensions of chemical information compared to just one to enable unambiguous drug identification,” he says, adding that MSI-CE-MS can provide even greater quality assurance by encoding mass spectral information temporally.

 Britz-McKibbin is currently completing a pilot study testing the efficacy of MSI-CE-MS on a cohort of 218 patients diagnosed with clinical depression at St. Joseph’s Healthcare Hamilton in Ontario. Researchers aim to determine whether this approach can tell psychiatrists which prescribed medications a patient is taking as well as any undisclosed harmful illicit drugs. This goal is challenging, since many patients are polydrug users and may be taking complex medical cocktails consisting of antidepressants or antipsychotics for some symptoms and opioids to manage pain. By sorting out all the agents that are present, MSI-CE-MS should provide new insights into optimal dosages and help to monitor unanticipated adverse effects, as well as confirming whether patients are adhering to their prescriptions and metabolizing the drugs properly.

As for how MSI-CE-MS fits into the opioid crisis facing Vancouver and other communities across Canada, Britz-McKibbin sees the technology playing an important role in forensic toxicology and therapeutic drug monitoring. The resulting analyses could help in assessing cause of death and identifying novel substances that may not be on the radar of physicians and others confronting street drug use.

“It’s important to identify emerging designer drugs, which could be novel fentanyl analogs that haven’t been reported to date,” he says. Additionally, routine drug monitoring of high-risk patients at methadone clinics can also prevent accidental drug poisoning by alerting staff to drug substitution and misuse.

Testing before taking

The fundamental importance of innovations such as MSI-CE-MS was highlighted this past December, when the British Columbia Centre on Substance Abuse launched a five-year project to study the effect and impact of drug detection on user behaviour. Because so much fentanyl is now in circulation, users are being encouraged to bring their drugs in for testing before consuming them. Insite, Vancouver’s oldest federally sanctioned supervised injection site, uses dipsticks and Fourier-transform infrared spectroscopy (FTIR) to test such drugs. Another injection site, the Lookout Housing and Health Society charity’s Powell Street Getaway, also makes FTIR available to individuals who anonymously submit samples of street drugs to be tested for opioids, stimulants and other substances.

Clinical biochemist Jan Palaty, who works at the Burnaby, BC location of LifeLabs Medical Laboratories, the province’s largest outpatient provider of lab testing, says liquid chromatography-mass spectrometry (LC-MS) would be an excellent complement to these current drug-testing strategies. Dipsticks and FTIR only register whether a sample tests positive or negative for fentanyl or its analogs; in fact, FTIR and commonly used colorimetric methods may not even register the presence of fentanyl in amounts below the methods detection limit. LC-MS, on the other hand, allows highly sensitive and accurate assays to be developed while measuring many compounds in a single analytical run. Crucially, LC-MS can not only detect the presence of a given compound but also measure the amount.

“No one in North America has done extensive quantitative testing, especially in the context of opioids,” says Palaty, who observes that simply knowing fentanyl is present does help you determine whether that means a tolerable proportion of 0.2 percent or a fatal proportion of 20 percent — a crucial distinction, to say the least. And its presence can now practically be assumed; a 2016 study at Insite found fentanyl in some 86 percent of the heroin, cocaine, methamphetamine and other substances that were tested. Given how often dipstick tests of users’ drugs will return a positive finding for fentanyl in users’ drugs, they may decide to take these drugs anyway, playing a kind of Russian roulette by hoping that the amount will be low enough for them to survive.

LC-MS also has the potential to detect other unknowns. “Hallucinogens like synthetic cannabinoids keep changing even more than fentanyl,” observes Palaty. “Mass spec can detect those, see what new drugs are in town, what new analogs might have shown up. Mass spec is so sensitive, it won’t miss much.”

For him a larger question is whether LC-MS can change behaviour and become part of overall harm-reduction strategies. Drug testing offers the added bonus of giving a healthcare worker the opportunity to engage the user in conversation and counselling, another cog in the harm-reduction wheel.

“If users learn on the spot that there is fentanyl in a drug, they’re unlikely to actually get off it or discard it, but at least they’ll typically reduce the dose,” he argues, adding that quantitative readings can generate even greater caution. “If you tell people how much drug is in there, well now you have a better chance of affecting behaviour.”

Although results from conventional LC-MS readings take a day or two, they can still establish a baseline for the drugs currently in circulation in areas like Vancouver’s Downtown Eastside, where a majority of the city’s illicit drug activity — and overdose deaths — take place. This information can alert police, safe injection site staff, healthcare workers, and other front-line professionals to the level of danger associated with the current street supply.

 Tallulah Photography

Vancouver’s poverty-stricken Downtown Eastside is Ground Zero for Canada’s epidemic of fentanyl drug overdoses. Photo credit: Tallulah Photography

Palaty and his colleagues in this field continue to work on innovative ways of making that supply safer for those who use it. He predicts LC-MS testing will be out dated in five years, when the bulky LC-MS equipment now in his lab will be replaced by point-of-care MS gear about the size of a suitcase. This has already been happening, he says, “as people realized that you could get perfectly adequate quality from a smaller, cheaper unit. It won’t be lab-level quality but in the classic triangle of speed, quality, and cost, all will be equivalent.”