Podcast: Injectable opioid agonist treatment for opioid use disorder: a national clinical guideline
Transcript
Kirsten Patrick: In our current reality of opioid crisis in many Canadian cities and towns, physicians are having to manage more and more patients with opioid use disorder. Contamination of street drugs with highly potent synthetic opioids such as fentanyl adds to the problem. Deaths from overdoses are increasing and so are the number of people with severe opioid use disorder. Some people with the disorder may benefit from injectable opioid agonist treatment rather than oral medications. I'm Dr. Kirsten Patrick, deputy editor for the Canadian Medical Association Journal. Today I'm speaking with two of the authors of a new Canadian clinical practice guideline on injectable opioid agonist treatment for opioid use disorder. The guideline is published in CMAJ. Dr. Nadia Fairbairn and Dr. Christy Sutherland are joining me from Vancouver to discuss it. Welcome.
Christy Sutherland: Hello.
Nadia Fairbairn Hello.
Kirsten Patrick: Can you tell us a bit about who each of you are? Christy, you go first.
Christy Sutherland: Sure. Yeah, so I'm a family doctor and an addiction medicine specialist. I work in Vancouver's Downtown Eastside, which we call Canada's poorest postal code. And I'm the medical director of a nonprofit to provide low barrier housing and harm reduction services. I'm also the physician education lead at the BC Center on Substance Use.
Kirsten Patrick: Go ahead, Nadia.
Nadia Fairbairn: Hello. So I'm a general internist specializing in addiction medicine. I practice at St. Paul's Hospital in downtown Vancouver, where I lead the Addiction Medicine consult service, which is staffed by 20 addiction medicine physicians. I'm also an assistant professor in the Department of Medicine at UBC, and a clinician scientist with the BC Center on Substance Use. I'm the principal investigator for the Canadian Research Initiative in Substance Misuse or CRISM, injectable opioid agonist therapy initiative. The purpose of the CRISM injectable treatment initiative is to assist regions with up to date information, best practices and recommendations and monitoring and evaluation to ensure a successful delivery of this treatment across Canada. And so today we're going to be talking about the clinical practice guidelines for injectable treatment that are part of that initiative.
Kirsten Patrick: So you're both very much on the frontline of this opioid crisis where you're situated. Can you tell us how things have been evolving what you've been seeing and where we're currently at?
Christy Sutherland: I can start so its Christy here, I can say that it's been an absolute nightmare. And I think that it's a horrific thing that Canada is going through right now. It's a national emergency with how many people have died. And it's especially heartbreaking to look at how young people are who have died. So we can see in BC that the average age is between 30 and 59, I think or 49. Like it's young people who are dying. And I think that makes it extra heartbreaking to think of the years of life lost. And the other extra heartbreaking thing is that every death is preventable that no one should be dying of opioid overdose. And yet we still see our loved ones dying and then Nadia and I see our patients dying of this preventable death. And it's heartbreaking and it is not getting better.
Nadia Fairbairn: Yeah, just to build on what Dr. Sutherland said. So that's 10 Canadians every day who are dying from drug overdose. And as she said, they're all preventable deaths. And what's driving epidemic is a poisoned drug supply. So we've seen this emergence of street fentanyl, carfentanil and other highly potent synthetic opioids that are increasingly cut into heroin and other street drugs. Last year alone, fentanyl and its related synthetic analogues were implicated in three quarters of all those opioid related deaths in the country. And it hasn't stopped there. So for example, there's been recent contamination of street drugs with benzodiazepine analog like etizolam. This is a drug that's regulated by Canada's Controlled Drugs and Substances Act because of its potential for abuse. And it's being found in substances sold as opioids. So it's really concerning. Given the known risks for respiratory depression, when benzodiazepines are consumed together with potent opioids in terms of risk for death, and we really are dealing with with a toxic drug supply. So we really need evidence based health services to address the harms related with untreated opioid use disorder.
Christy Sutherland: And I would add to that and say that it's people who had opioid use disorder who are being affected. But its people with alcohol use disorder, stimulant use disorder, and people who don't have any addiction at all, anyone who uses drugs in Canada, and I mean, that's lots of us, and it's a regular thing to do as part of being a human is to use drugs is at risk of death because of this unregulated market that is so dangerous.
Kirsten Patrick: Those statistics are shocking. I had no idea that the tainted drug supply was responsible for so many deaths. So the guideline that you've developed who is it for?
Nadia Fairbairn: So Dr. Sutherland and I are really happy to share with you that a guideline because it provides a roadmap for clinicians who treat patients with opioid use disorder on how to prescribe injectable opioid agonist therapy for their patients who might benefit. And this is one treatment approach that represents potentially one impactful response to the opioid crisis. So this document is written for Canadian clinicians. That is our target audience. There is an evolving landscape for opioid agonist treatments in Canada. So traditionally, in the past, there's been a lack of uptake of newer treatments, because there haven't been guidelines to support implementation of clinical practice in the field of addiction medicine. So this is one emerging treatment in Canada, and one that we can look to expand as a response to the overdose crisis. It's an evidence based cost effective treatment for individuals with severe opioid use disorder who haven't benefited from other treatments in the past.
Christy Sutherland: Sometimes at first glance, it can be hard to wrap your head around why giving people who inject drugs, drugs to inject would make them better. But it really does work. And as a clinician, I can say it's a joy to deliver the service to my patients, because watching people who have been struggling for years with opioid use disorder, have not been having success on traditional oral treatments, suddenly get better, is just a wonderful thing. You know, to walk with patients along that journey as they figure out their goals and their next steps in their life and they obtain housing and obtain employment and reconnect with families. It's a really wonderful clinical intervention to be able to offer. And I think it's the same sort of steps that when methadone first came out as a treatment for opioid use disorder, it seemed contraindicated or seems kind of funny to wrap your head around to give opioids to people with opioid addiction. But we have so much evidence that methadone makes people live a better life and live longer and have better outcomes for all of their clinical conditions. And that the IO literature is actually quite robust as well. The first study was done in 1994. So we can say that this is a really great clinical intervention for people who need it. And as a clinician, I can say it's been wonderful to be a prescriber.
Kirsten Patrick: Can you explain briefly how this guideline was developed?
Nadia Fairbairn: I'd like to start by describing why we believe the development of the guidelines is so important, and then talk a little bit about the development process. So you know, as practicing clinicians, we know that clinical guidelines are essential resources for us, and to provide concise instructions on how to provide a health care service. The most important benefit of a clinical guideline is to improve quality of care and patient outcomes. So Dr. Sutherland and I have both had the good fortune to see what an incredible difference this treatment makes for patients. And this guideline can help translate that into practice for other physicians so that they can similarly have those experiences with the patients that they care for. I can give you an example. And this was a patient that actually I shared with Dr. Sutherland. This patient was in hospital at St. Paul's hospital where I practice and was in with a severe infection with infective endocarditis, and had left hospital multiple previous times due to addiction related circumstances, I had not been able to titrate to a adequate dose of methadone or buprenorphine/naloxone, which are our first line treatments in Canada, and was started on injectable opioid agonist treatment in the hospital stabilized very well and managed to finish that whole six week course of antibiotic treatment and was transferred over to Dr. Sutherland's clinic where he continued to do really well get care and housing and all the other important benefits that come with being a stable from a substance use perspective. So this guideline aims to fill this important gap by giving this roadmap to clinicians in terms of how defining who will benefit from this treatment and how to actually prescribe it. So in terms of the actual guideline development process, the guidelines were developed by the CRISM CIHR funded research network, there was no pharmaceutical industry support. And in terms of the scope, the clinical guideline itself provides three key recommendations. They're focused on the patient population that should be considered for injectable opioid agonist treatment. So who should you consider starting on this treatment, as well as which medication to select and how long treatment should last? So this document also contains some experts opinion on clinical care approaches, and like eligibility titration and how to manage missed doses. In terms of the process, this project was a national initiative so we convened an expert's interdisciplinary committee that had 32 individuals who all brought a unique expertise and experience to the guideline development process. So that included experts with a range of lived experience and different backgrounds like physicians, nurses, pharmacists, people with lived experience, researchers and frontline staff, and then myself and Dr. Sutherland co-chaired the committee. We manage competing interests using guidelines International Network principles for disclosure of interests in management of conflicts and guidelines. And there were no current or ongoing, direct competing interests disclosed by any of the 32 members on the committee. And then we applied the grade criteria in doing a structured literature review to appraise all the literature and come up with a series of recommendations. These recommendations went through several rounds of review with the committee until we were all agreed upon by committee consensus. And then in addition to the recommendations, we added clinical guidance based on expert opinion, after we were happy with the guideline, and as a committee, it went through a last round of review with 10 international experts prior to finalization. So these guidelines were developed using the theme rigorous industry free approach that's used in other clinical guideline development for other common chronic medical medical conditions we frequently encounter as clinicians, which is why we're so pleased to be able to share them with other Canadian clinicians.
Kirsten Patrick: So on to the guideline recommendations, you have three key recommendations, let's go through them. The first has to do with how physicians can best determine which patients are good candidates for injectable opioid agonist versus oral agonist treatment. What is the guidance there?
Nadia Fairbairn: So absolutely, we can review the three key clinical recommendations in the guideline. So the first recommendation is that injectable opioid agonist treatment should be considered for patients who have severe treatment refractory opioid use disorder and ongoing illicit injection opioid use. So they have to be a person who injects drugs, who have a severe opioid use disorder and have not previously benefited from other treatments, like methadone or buprenorphine/naloxone. So this recommendation is based on meta analyses systematic reviews of clinical trials involving patients with long term refractory heroin addiction. And as Dr. Sutherland mentioned earlier in the interview, there's actually a very robust evidence base for injectable treatment. It's very common treatment in Europe. For example, in the UK, this treatments been provided for over 100 years in an unsupervised setting and then since 1994, and in Switzerland as well. So these studies have demonstrated efficacy for medical heroin therapy in comparison to methadone for reducing illicit heroin use, criminal activity, reducing involvement in sex work, as well as improving overall health and social functioning in other in other locations. And then hydromorphone, the other medication option has been shown to be similar to injectable heroin therapy in terms of retention rates, reduction in street opioid use and illegal activities. So in terms of patients likely to benefit your we're thinking about patients with severe opioid use disorder who inject opioids and have not been successful with past treatments.
Christy Sutherland: Yeah, I think that this is one of the key things for clinicians when we're offering a new intervention is who needs this intervention? And who doesn't need this intervention? I think about the addiction community. We're like a bunch of cardiologists when beta blockers were invented, to figure out like, how do we use this new intervention. And I have found it to be really wonderful to integrate this into my practice. And I very rarely disagree with a patient about whether or not they need injectables. And it's a wonderful sort of collaborative decision making process you can make along with your patient as you describe the program and what's involved and the purpose and the goal, and then decide together whether that's a good intervention for them. One of the things I was worried about, and I think that funders and public bodies and the public were worried about when we started injectable programs is that every single person would want to be on this and every single person would want to be on it forever, and every single person who would want the maximum dose. And I have not at all found that to be true in my clinical experience over these past three years, that people patients are very thoughtful about what intervention that they want. And that it reminds me a lot of my methadone practice where often I'm trying to get people to go up on the dose and get people to stay on the intervention longer to give them a bit more times to taste to stabilize, and so that those fears really haven't come to play in clinical, the clinical setting. And I think that that comes down to patient selection, that it's a collaborative process between a physician who they trust, and the person who's with living their own life when they decide what what they need for themselves for their health.
Nadia Fairbairn: And just to build on Dr. Sutherland's point that is really borne out in the literature. So in other settings across Europe, for example, where that have really established programs, it's estimated it ranges between 1% and 15% of patients with opioid use disorder who select this treatment and and are on this treatment. So it is a specific kind of sub population of people with opioid use disorder who really benefit and there's lots of reasons for that one, main, really big reason is the intensity of the treatment. So this is something where people are going to some sort of health care facility, whether it's a clinic or a dedicated facility to have a supervised injection of the medication two to three times a day, typically. So that's really a large part of their daily activities is visiting a clinical setting. And so for many people, they'll stabilize and it'll make a really big difference for them in terms of getting on to this treatment. And then they'll look to want to reduce the amount of time they're, they're spending at a clinic because they have other things to do, be with reconnect with family work, etc. And they'll wish to deintensify treatment to an oral medication or something else.
Kirsten Patrick: This is really interesting to me, this is not my field at all. I do want to ask you about cost of an injectable opioid agonist treatment versus oral, what's the cost difference?
Nadia Fairbairn: So there, I can speak a little bit to that, and I'm sure you will, too, Christy. So in terms of the cost effectiveness of this treatment, there's also really good evidence around that. So there have been cost effectiveness studies conducted both in Europe as well as in Canada. They have found that injectable heroin treatment as is much more cost effective than oral methadone, due primarily to significant reductions in criminal activity and the costs associated. There have also been cost effectiveness studies looking at the other medication type, the hydromorphone, and it's also been found cost effective compared to oral methadone treatment, because of reductions in criminal activity as well as hospitalizations and the associated costs with needing health care. So we know that it's a cost effective treatment for people who are a good fit for for this intervention.
Kirsten Patrick: Yeah, I guess, selecting who is a candidate for the treatment is is key.
Christy Sutherland: Yeah, absolutely. I'm always someone like, obviously, with my heart. And so I always think that the clinical outcomes are what matters most. And the cost is always second to me. But it's always nice to see in addiction medicine that, you know, harm reduction and Addiction Medicine services are really our money saving interventions for the system. But I think it's hard from a resource allocation perspective that the money saved is often in the criminal justice system. And then you don't get that back from the Department of Justice to spend on more health care interventions.
Kirsten Patrick: That's the tricky thing, isn't it?
Christy Sutherland: Spend so much of my time doing low barrier housing, we do needle exchange, we run supervised consumption sites, so many things that save the system so much money, but I'm not getting that money back.
Nadia Fairbairn: And just to add to that, one thing that often comes up is actually specifically looking at the cost of the medications. And that's a moving target in Canada and something where there may be changes in the future, especially if we do expand access to this treatment. So to give a couple of examples, injectable heroin therapy just in April of this year was added to the drugs for urgent public need list for the whole country, which may facilitate access. And with expanded access, it may be possible to lobby or advocate for having a Canadian focus supplier, which would have a huge impact on the cost of medical heroin therapy, the medication cost itself. And then similarly for hydromorphone, Health Canada recently approved injectable hydromorphone for treatment of opioid use disorder. So previously, it wasn't indicated for that. And it now is indicated for severe opioid use disorder. And so again, that may lead to some potential opportunities for negotiation around drug costs with expanding treatment access.
Kirsten Patrick: Are there any patients who are not good candidates for this particular therapy? Perhaps pregnant women, youth or patients who are taking other drugs?
Nadia Fairbairn: So that's a great question when it's so important that we always match any treatment plan to that individual patient needs. So there's never kind of a one size fits all. So there are some populations that require special consideration. The guiding principle here though, is that we always need to tailor our treatment options to that individual patient, we need to carefully weigh the potential benefit and the risks of providing or not providing a particular treatment for a patient. And that's really important to bear in mind in the context of the toxic illicit drug supply where people are at such great risk of harms and including overdose deaths when left untreated. So in the guideline itself, we acknowledge that to date, there's very little published evidence on injectable opioid agonist treatment in certain special populations. So those would include youth under 25 years of age as well as pregnant in the case of pregnancy. So when it comes to youth, the guideline recommends that caution should be exercised when prescribing in people under the age of 25 because of the limited evidence in that patient population, and that it's super important in this case to make any treatment decisions in consultation with a team of providers. So you'd work with other health care professionals with experience and treatment of adolescents and young adults with substance use disorders. And it's really important that clinicians use all available information and their best judgment when considering treatment options for someone who's at high risk for overdose death. In the case of pregnancy, the guideline also stresses the need to exercise caution in pregnant people or people who become pregnant who are on injectable treatment. So we do definitely need more research in this area, in order to have clear clinical recommendations. And again, we emphasize the need to weigh the potential benefits and harms of starting a treatment versus not offering that treatment to a patient. There are a couple of case reports showing beneficial outcomes for for mom and for baby in patients who were prescribed injectable treatment through their pregnancy that are out of Europe. And I don't know maybe Dr. Sutherland wants to give an example if she's had many patients herself, in the case of pregnancy.
Christy Sutherland: Yeah, I won't give a specific example. For me, it's really a human rights approach to how we treat pregnant women that they deserve the standard of care. And so that's the philosophy I always take when I'm treating pregnant people who use drugs. I think also, the clinical decision making gets a bit more challenging. And it's the same, I think, for policy and how we're, as physicians across the country that overlap between addiction and chronic pain, where this intervention is a high intensity intervention for people with opioid use disorder that has been refractory. And that is not meant for a chronic pain population. But sometimes people who identify as having chronic pain are using fentanyl from the street and overdosing. And so that's where it can get complicated when you're doing your intake assessment and getting to know a person over time of teasing out that diagnosis of a chronic pain patient versus someone with substance use disorder and whether this intervention will be beneficial for them. But I think that's part of a larger conversation that we're having as clinicians and policymakers about this intersection, and that how vulnerable each of these populations are and how much overlap there is between these populations.
Kirsten Patrick: So for patients who are determined to be likely to benefit from injectable opioid agonist treatment, which you've said is, is on a case by case basis, what then are the medication options?
Nadia Fairbairn: Yep, so there are two options. The first option is diacetylmorphine. That's also known as medical heroin. And the second option is hydromorphone. And the short answer is that both hydromorphone and diacetylmorphine or medical heroin can be considered a reasonable choice when prescribing injectable treatment.
Kirsten Patrick: So now I question if you've got two options, how do you make the choice? Is it, do you make it in collaboration with the patient? Or are they different kind of side effects or effects of each of those medications?
Christy Sutherland: Right now, it's an issue of access that we only have access to hydromorphone outside the specific Crosstown clinic that was the original site of the study of heroin assisted treatment here in Canada. And so I don't actually have the option to offer it clinically in community to have the choice between hydromorphone and heroin. I think that heroin has more evidence to support its use, and that my patients report that they would prefer heroin. And I think that that makes sense. Because when we look at the receptor in someone's brain, and we look at what the molecule is that they are used to having occupy that receptor, if it's been 20 years, that's these subtle changes between heroin and hydromorphone, even though they're both opioid agonists, can be felt by that person. And so I think that we need to really meet the patient where they're at is what we say in harm reduction, and give them the molecule that's closest to what they have been used to using. And I think when we look at the heroin literature in Europe, it was heroin assisted treatment was done in a heroin context. And in Canada right now we're offering hydromorphone in a fentanyl context. So there is a leap to be made from the randomized control trials that we have to how we're practicing it clinically.
Kirsten Patrick: That's actually a fascinating insight into the intersection between the evidence and real life practice. The third recommendation in the guideline is related to ongoing management and treatments end date. What does the guideline recommend?
Nadia Fairbairn: So the third recommendation gets to the issue of treatment duration when starting someone on injectable therapy. And the takeaway here is that injectable treatment should be provided as an open ended treatment with no fixed end date. So that's the key recommendation. The guiding principle is that decisions when transitioning to oral treatments should be made collaboratively with the patient. And that's based again on a fairly robust studies in Europe that show that if people have a predetermined end date for this injectable therapy, when they transition onto oral treatment or off of injectable, they tend to go back to baseline levels of substance use. And that happens quite quickly, usually within a few months. So based on that the recommendation is that this should be an open ended treatment. That being said, people definitely choose to transition off of this treatment. Voluntary transition happens for sure, about 30% of people self select to transition to an oral treatment every year, some transition back onto injectable therapy at other times others don't. And it's all really part of offering that full continuum of care to patients.
Christy Sutherland: For me, this recommendation, and what is shown in the literature really makes sense as a community family doctor, where I have a longitudinal relationship of trust with my patients, and I want them to feel safe to change the treatment that they're on knowing that they can restart it. So for the injectable program I'm running in community, people can go on and off it as many times as they want. I say you get as many kicks of the can, as you like for trying oral treatment alone. So they're not afraid to switch to oral alone and see how it goes. As well, they're still within my continuum of care. So I continue to be their family doctor, whether they're on the treatment or not. So they're still engaged and be able to get their Pap tests and their LIPITOR refilled all of those wonderful primary care things at the same time. And I think it makes sense that it needs to be in the patient's hands to decide when they're done with an intervention like this, that we can't predict when someone might be done.
Nadia Fairbairn: And again, just to draw parallels to any other treatment that we offer in medicine, that's, you know, really common that we will go over a person's course of illness with a chronic illness, or their treatment plan will change and adapt based on their circumstances and their needs. And so that's why it's so important that this be offered as an open ended treatment.
Kirsten Patrick: Does the guideline offer any practical advice for clinicians or health services that are trying to set up a clinic of the kind that you have described?
Nadia Fairbairn: So the clinical guideline itself is being published in CMAJ and it's being released. And to go along with that we've also developed a partner document, which is an operational guidance document for people working in health services that really provides a roadmap for them in terms of if you were to start a program like this, what are all the considerations that need to go into setting up a clinic, designing the model of care, staffing it, procuring medications, and things like that. So coming out with the clinical guideline for clinicians in terms of how to prescribe is is also this Compendium document that we hope will be really useful to be used in tandem, in terms of really increasing access to this treatment in Canada.
Christy Sutherland: I think it might seem like an overwhelming intervention to initiate in a clinical practice, especially as a family doctor, but I would encourage clinicians to check out our guideline and our operational supporting document. And to really think that it's not that overwhelming, actually, and that even if you only have one or two patients who would benefit from this intervention, it's worthwhile thinking through if you can offer it because it works so well for the people that it does work for.
Kirsten Patrick: One last question unrelated to the guideline. In your opinion, what do you think needs to happen for us to curb or eliminate the opioid crisis in Canada?
Christy Sutherland: I think that in order to stop these deaths from opioid overdose, we need to end the war on drugs. So the first step would be decriminalization. And decriminalizing is a sort of easy step. I think that you just decrease the scope of practice of police to say that possessing drugs for personal use, not for trafficking, for just recreational personal use is not a crime, you shouldn't have to go to jail. And this would free up so much police resources, it would free up so much money, it would declawed prisons for people, I can't imagine people being in prison for just possessing a half a gram of cocaine, like it's pretty ridiculous, really, when you think about it. And then as well, when we think about policing, we know that it's not representative of what it should be in terms of race, that people of colour and indigenous people are dramatically overimpacted by being criminalized for using drugs and that white people are more sheltered from those negative consequences of personal drug use. So I think decriminalizing is the first step. And then we wouldn't have this log as clinicians on the forefront of our patients being in and out of jail for these nonviolent drug possession crimes. And we know going in another jail increases your risk of death, and increases your risk of HIV. I think once that's happened, we have a space to create, like a really nice future state that is ideal in terms of a legal regulated drug market. We know that this is the safest from a public health perspective. What we have now really is the worst thing that you could pick where we have incredibly profitable, organized crime, trying to sell drugs, to as many people as they can, with only profit as their motive. So like if I were a parent, I would really want a legally regulated drug market because right now drug dealers are trying to sell to use in order to make more money. But if we had a regulated market, youth would be much more protected actually from initiation of drug use. And when people think about illegal regulated drug market, often they think of the liquor store, but the liquor store is not actually the ideal circumstance for how to sell drugs. That we can pick for each substance what is the best model in order to safely provide it to people who are already using drugs and to screen out use and new people initiating drug use.
Nadia Fairbairn: Yeah, I fully agree with what Dr. Sutherland said, you know, we really, we really need to think about how history is going to look back on this era where we're losing so many Canadians to a totally preventable cause, like opioid fatalities. We need to be pragmatic and responsive, and we need to regulate the drug supply. I really think that is a crucial step. for clinicians. I think we need to advocate for a system of care that provides comprehensive, collaborative, compassionate and evidence based health services to address the harms of the opioid crisis. We hope this guideline and the associated toolkit that we've put together on injectable treatment for opioid use disorder will be an important way to advance this cause and better meet the needs of our patients.
Kirsten Patrick: Well, thanks for talking to me today about this amazingly useful guideline that will benefit so many clinicians across Canada.
Christy Sutherland: Pleasure. Thank you so much.
Kirsten Patrick: I've been speaking with Dr. Nadia Fairbairn and Dr. Christy Sutherland. Dr. Fairbairn is an internist who specializes in addiction medicine at St. Paul's Hospital in Vancouver, and is director of the International Collaborative Addiction Medicine Research Fellowship with the BC Center on Substance Use. Dr. Sutherland is a family physician in downtown Vancouver, who specializes in addiction medicine. She has led a number of initiatives to help downtown Vancouver's most vulnerable residents. To read the Canadian clinical practice guideline on injectable opioid agonist treatment for opioid use disorder, visit CMAJ.ca. Also, don't forget to subscribe to CMAJ podcasts on Soundcloud or podcast app and let us know how we're doing by leaving a rating. I'm Dr. Kirsten Patrick, deputy editor for CMAJ. Thank you for listening.