Research As It Happens: Positron emission tomography (PET) imaging study looks at chronic pain and potential indicator of opioid addiction risk

What you need to know

Of the 1.2 million Canadians taking prescription opioids for chronic pain, more than 10 per cent develop opioid use disorder compared to just 0.2 per cent in the general population. Currently, it is unclear which neurochemical factors put them at risk.

The brain contains an endocannabinoid system that has the enzyme fatty acid amide hydrolase (FAAH). This enzyme is linked closely to a greater risk of addiction and a greater perception of pain. Based on results from animal studies, researchers believe that people with opioid use disorder may have less FAAH enzyme in their brains compared to people without this condition. But the relationship between the endocannabinoid system and opioid use is poorly understood.

In this issue of Research As It Happens, we present an interview with Dr. Isabelle Boileau and PhD candidate Claire Shyu. Together with Dr. Bernard Le Foll, Dr. Andrew Smith and their colleagues at CAMH’s Interprofessional Pain and Addiction Recovery Clinic (IPARC), they are examining whether FAAH could help identify people at risk of developing opioid use disorder. They also hope to see whether therapies that target the endocannabinoid system might have the potential to treat chronic pain. Dr. Boileau, Dr. Le Foll and Claire Shyu’s study is funded by the Canadian Institutes of Health Research (CIHR).

This interview was edited for clarity and length.

What is this research about?

Claire Shyu: There is evidence showing that a lot of people taking prescription opioids go on to develop opioid use problems, yet we’re also seeing that some people who are using opioids long term do not go on to develop opioid use problems. So, we’re trying to understand whether there are neurochemical differences between these two groups, to see if there are biomarkers [i.e., some sort of unique molecule or biological factor] that would help us prevent chronic pain patients from developing opioid use disorder.

The reason we’re looking at FAAH is that it’s been implicated in pain and it has been implicated in addictions. Specifically, some people with lower FAAH activity have been found to be at increased risk for developing alcohol use disorder and cannabis use disorder. So we want to see whether there’s also this trend in opioid use disorder.

Dr. Isabelle Boileau: The idea to look at FAAH as a potential biomarker for those that are at risk for developing opiate use disorder definitely is the main aim of the work. The other aim is to see whether therapies that target the endocannabinoid system might have some potential in people that are seeking treatment for chronic pain. FAAH inhibitors are experimental drugs that have been tried for the treatment of pain in humans. And while these studies have not been successful, we feel there might be other types of pain for which these medications might be beneficial. Learning more about the endocannabinoid system in humans can also help us develop ways to use these medications in a better way. In fact, some animal studies have shown that giving drugs that target the endocannabinoid system in conjunction with opiates might lead to better treatment and fewer withdrawal symptoms from opiates.

Who is conducting this research? 

Isabelle: We —Dr. Le Foll is the qualified investigator in the trial—are leading the study, and our collaborators from the University of Toronto are Rachel Tyndale, who is helping us with some of the genotyping, as well as Dr. Richard Bazinet, a collaborator in the Department of Nutritional Sciences at CAMH, who is also doing some of the analysis of endocannabinoids blood levels.

Claire: We’re also collaborating with Dr. Andrew Smith and Dr. Rachael Bosma from the Toronto Academic Pain Medicine Institute, who are referring patients for the study.

Where is this study being done? 

Isabelle: We’re doing it at the CAMH Brain Imaging Centre. The interesting aspect of our work, which we’ve leveraged across different studies, is the use of PET [positron emission tomography] imaging using probes that specifically target the endocannabinoid system in the brain. The technology is unique because it allows us to look at the FAAH enzyme in the living human brain and this is something that isn’t being done anywhere else, as far as we know. Developing probes for the endocannabinoid system is very expensive, it’s a significant enterprise. We developed this technology more than ten years ago and have been able to lead the way in understanding the role of FAAH in the living human.

Who are the study participants? 

Claire: We’re recruiting two groups of chronic pain patients taking prescription opioids regularly—that would be daily or near-daily use—for pain. In one group, participants have a history of opioid use disorder and are taking opioid agonist therapy with either buprenorphine or methadone (These are opioid medications for treating opioid use disorder). In the other group, participants have never had a diagnosis of opioid use disorder. Our goal is to recruit 30 participants in each group.

What study methods did you use? 

Claire: First, we do a screening visit and collect the medical, psychiatric and drug use history and we do a broad-spectrum urine screen to determine the person’s eligibility to enrol in the study. Each enrolled participant then completes a PET scan, looking at the FAAH enzyme, an MRI scan and a battery of neurocognitive tests, looking at addiction-related behaviours and phenotypes [which are the observable characteristics in a person that result from the expression of their genes]. We plan to complete the study by the end of 2024. We’re still in the process of looking at our preliminary data and understanding the trend and seeing if there’s an opportunity to expand to a larger sample.

Isabelle: The idea is to collect the data and see if the study is feasible and if there’s a signal [an indication that there might be a difference between the two participant groups], and then apply for another grant. We have funding for this study from CIHR. But now that we’ve run through the protocol, recruited the population and actually have a very interesting signal—one that’s in a completely different direction than we expected but nevertheless a very interesting finding—we plan to apply for funding to the NIH [National Institutes of Health] to do a full-scale study. This would probably mean increasing the sample size and recruiting a group of participants who have chronic pain and are not taking opiates. To have a full design, we would need this additional group.

We’re at the stage now where we can actually calculate how many cases we would need to have a statistically significant effect. This will help us see how many cases we would need to have a definitive finding.

I think one of the most interesting and important things is to see how this enzyme relates to behaviour. So Claire is in the process of looking at whether FAAH levels in the brain are in any way related to pain, mood or urge to use. I think we will be able to flesh these things out for the NIH grant to address this question.

This study is part of a larger program. It all started several years ago when we developed this PET probe at CAMH to look at FAAH and applied it to different conditions. The first question we asked was whether or not FAAH was related to cannabis use disorder, and this is more of a basic research science question. And then we looked at other conditions, including alcohol use disorder and post-traumatic stress disorder.

We are conducting more studies focused on understanding the endocannabinoid system. But this one is the first to look at the link between the endocannabinoid system and opioid use disorder in the living human brain.

What is the desired outcome of your research? 

Claire: Ideally, we would like to see a clear separation between the two groups of participants and see if we could use FAAH to potentially identify if a person has the tendency to develop opioid use disorder. This could give a clinical team an idea of who might be at greater risk, which could help mitigate what is going on with the opioid overdose crisis.

What are the limitations to your study? 

Isabelle: There are many but, primarily, it is that the population that Claire is studying is a very complex group. I think participants will be very different, one from the other, for example, in terms of the types of pain they have, the sex/gender differences, and the medications they’re taking. So, it’s going to be a challenge to disentangle what is actually accounting for the differences in FAAH.

I think the more generic problem is that when we do find these differences in FAAH, we won’t know if the difference contributes to opioid use disorder or if it’s the result of the brain compensating for something. I think it will take some time to develop working models of this. Not just time but also different probes.

In this study, we’re looking at one little snippet, the FAAH enzyme in the brain, but it would also be a good idea to look at the endocannabinoid receptors and other enzymes to have a more fulsome view of the endocannabinoid system. And our brain centre is the perfect place to do this. It’s just a question of time and money. In fact, it’s a wonder that nobody has ever looked at this question, that there aren’t any studies looking at the cannabinoid receptor or at the FAAH enzyme, because they’re implicated in pain and they’re implicated in addiction. So, it’s an exciting field and an exciting time for this type of work.

What will the research potentially add to the sector?

Isabelle: It will provide a first, basic look at the endocannabinoid system in the brains of people with opiate addiction. I think this is a basic research science question that will trigger more interest in this area and stimulate more research in this area—looking at the other aspects of the endocannabinoid system—research that I hope our centre will be able to do. The endocannabinoid system is a big player in pain, and it hasn’t been studied in humans.

Are there any identifiable future areas to build on this research?

Isabelle: I hope it will have some applicability. I think it will take some time to try to see how, potentially, FAAH or endocannabinoid therapies might be beneficial or not for people that have chronic pain. That is the hope. And because of this tool [PET imaging probes], if there is a trial looking at the effects of FAAH inhibitors in this population, we’re going to be helpful in guiding this research, in deciding which populations might benefit from these medications. But this will take time. We’re not there yet.

Are there any future areas you would like to get into once this study is over?

Claire: Like Isabelle mentioned earlier, it would be interesting to look at different chronic pain populations, given how complex the cases we’re already seeing are. We know that the underlying physiology of pain is very different across different pain types. So it would be interesting to see whether there are group differences between these patients.

Isabelle: We’d like to expand the study to people who are not receiving opiates as the main treatment. To look at other aspects of the endocannabinoid system, which will become possible at CAMH soon. Other aspects, such as trying to use FAAH as a biomarker of addiction risk, are not very applicable in the clinic because PET imaging is too expensive to allow clinics to scan all their patients with these probes.

However, in our current study, through our collaborators in nutritional sciences, we’re taking other measures that may be useful stand-ins for the FAAH enzyme. And, of course, if we look at the deep phenotyping that we’re doing in these individuals, linking phenotypes with what’s happening in the person’s brain, it will also be useful and more applicable in the clinic.

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