Opioids for Breathlessness: A Podcast with David Currow

Eric: Welcome to the GeriPal Podcast. This is Eric Widera.

Alex: This is Alex Smith.

Lynn: And this is Lynn Flint.

Eric: Alex. We have somebody very, very, very special online with us.

Alex: We have a world famous palliative care researcher. We have Professor David Currow, who is from the University of Technologies Sydney, Australia who is actually in Hull, England visiting a collaborator right now, and he joins us on the Skype line. Thank you so much for joining us, David.

David: Great to be with you.

Eric: We’re going to be talking about breathlessness, managing things like dyspnea in palliative care populations and we’re going to be talking about one of David’s recent articles in Thorax about, Sustained-release Morphine for Chronic Breathlessness. But before we do, we always start off with a song request. David, do you have a song request for Alex?

David: Well, Every Breath You Take by The Police has to be today’s song request really, doesn’t it?

Eric: That’s perfect.

Alex: [singing] “Every breath you take, and every move you make, every bond you break, every cake you bake, I’ll be watching you.”

Eric: Every cake you bake?

Alex: You didn’t know that?

Eric: I didn’t know.

Alex: I was practicing this song last night and my younger son says, “What is that song about? Is that about Santa Claus? Like, I’ll be watching you all the time?”

Lynn: Oh, It’s a little creepy.

Eric: It’s very creepy. It’s a creepy song. But we’re not going to be talking about the creepiness aspect of it. We’re going to be talking about the breathlessness aspect of it. David, I’m really excited. For those listeners who don’t know, you’ve done some really pivotal studies often maybe turning around a little bit about what we do in palliative care. So, oxygen for everybody with breathlessness, maybe that doesn’t work. Octreotide for individuals with malignant bowel obstruction. Maybe that doesn’t work. Antipsychotics. Maybe that doesn’t work for delirium in palliative care populations and now opioids. Wait, before we actually talk about do opioids work for breathlessness in palliative care populations, how did you get kind of interested in this as a subject?

David: I think breathlessness has been a Cinderella topic for a long time, and if we wind the clock back 40 years, when someone came in with cancer and said “I’ve got pain.”, their clinician said, “Well, of course you do. You’ve got cancer.” And unfortunately, we still do exactly the same when someone comes in and says, “I’m breathless.” People shrug their shoulders and go, “Well, you’ve got Chronic Obstructive Pulmonary Disease. What do you expect?” rather than saying, “How do we deal with the symptom? Particularly of chronic breathlessness. Breathlessness that is unremitting.” And so, that’s what I’ve been working on with a team really right around the world over the last few years.

Alex: I want to dive into talking about why this particular study was needed. In a clinical practice, when I’m seeing somebody with breathlessness, I first will suggest non-pharmacologic interventions, but often those are insufficient at least for the severity of patients I’m seeing. And to be fair, I see patients who are hospitalized and they tend to have very severe breathlessness. And so I will prescribe opioids and sometimes long acting opioids. I’m interested in your sense of whether this is sort of standard practice that this article is evaluating and potentially challenging here?

David: As you point out, we have a responsibility to make sure that the reversible things are reversed and that paper by Deb Dodgen 20 years ago suggests that we shouldn’t assume that everyone else is looked for the reversible causes. The non pharmacological therapies are crucial and really as you move to pharmacological therapies we have statements from The American College of Physicians, the American College of Chest Physicians, the Canadian Thoracic Society, the European Respiratory Society suggesting that opioids have a role, and I think this is somewhat different to the other studies that you cited a little earlier Eric, in that there is a body of work out there already. There are meta-analysis that have been around for 20 years, and we need to take this study in that context.

David: By contrast, if we take the oxygen study there really was nothing else that had been done of that magnitude in the palliative care population, and so this study needs to be taken in that context. This is one paper from the study and there are several other papers that are already following. The Toxicity Paper, the Harms Paper is already out there and importantly that’s showing no excess signal of harms other than constipation and vomiting. So, we’re again reinforcing the meta-analysis from Daisy Janssen’s Group a couple of years ago that there are no respiratory signals from using regular low dose, sustained-release morphine for the reduction of chronic breathlessness.

Eric: And if you had to summarize… Oh, we’ve got a lot of feedback all of a sudden. Do I still hear it? No.

Alex: No, it’s gone.

Eric: Do I still hear it? No, okay. If you had to summarize the evidence for its effect on breathlessness up until this point, would a reasonable statement be that small studies including like the Abernathy study, which you were on right? Suggests that long acting opioids in small doses can have a positive beneficial effect on breathlessness, and there is very few studies on short acting opioids for breathlessness.

David: Absolutely right. If we look at the couple of meta-analysis by Magnus Ekstrom in the last few years, the one that was published in 2015 I think, in the Annals of the American Thoracic Society is an important one because we moved from just looking at everything that was done to including only studies that got to steady state, and then looking at by disease in the analysis, and that was a strongly positive study as was a subsequent meta-analysis published by Magnus a couple of years later. So we’ve got several meta-analysis that show that systemic opioids, and specifically morphine and we’ll come back to that because there are some other interesting papers that have come out over the last 12 or 18 months, have a symptomatic benefit that is safe and without signal of respiratory depression.

Eric: Can I push you on… you said reaching a steady state? Do you mean long acting opioids that are given daily versus like a PRN short acting opioid.

David: Or the single dose studies. There were a lot of single dose studies way back in the 80s and 90s that have made it into some of those meta-analysIs. As we did with pain, we needed to think about those studies differently. Because at the end of the day, single dose opioids are unlikely to have an effect if we think about both the pharmacokinetics and indeed the pharmacodynamics.

Eric: Why is that? Because I think like I see a lot of people… Alex, do you start off with like a PRN morphine?

Alex: I do before I Institute long acting. I could start off with a short acting. Lynn?

Lynn: Yes.

Eric: Is Alex doing something wrong?

David: Oh god, no. Alex is a saint, that’s easy. But you may want to look at the literature, when again the majority of the studies are done with people who are opioid naive starting a low dose of sustained release morphine. And when we look at the pharmacokinetics, the peaks are lower the troughs are higher than if you use immediate release morphine solution or immediate release morphine tablets for example.

Eric: Yeah, I think the problem is we get kind of screwed in America because we only have the 15 milligram twice a day formulation of morphine, in most places of long acting morphine. It’s really hard to get, to start somebody on 30 a day who’s opioid naïve of long acting, plus now we have guidelines saying ‘Don’t start long acting’s unless they’re none opioid naive,’ mainly for pain. But I think a lot of people also think about that for dyspnea as well.

David: If I have access to 10 milligrams per 24 hours and 20 milligrams per 24 hours so, that makes an enormous difference.

Alex: Huge difference. Yeah, I’ve lamented this, I give talks about opioids for pain and breathlessness. We need a lower dose long acting formulation.That’s the primary reason why I start with short acting doses usually PRN, but sometimes around the clock.

Lynn: Yeah, I usually start with a short acting dose and check in with the patient about how they feel and titrate based on that sort of very quick and of one experiment.

Eric: Why from a pharmacological standpoint, is that potentially not a good idea?

David: Well, again if it’s just PRN, then you’re not going to have a background level, if you’re using it early it’s going to be some time before there’s an effect. Particularly if you’re using it for emergent breathlessness or even for planned function, the peaks are 30 to 60 minutes after you’ve taken that and if there’s no background on which to build, you’re really starting from zero each time. In chronic, I think the point here is that chronic breathlessness is with people all the time. I really like the Australian author Tim Winton’s view on this, “You never think of breathlessness until it’s all you think about”. I think we underestimate the lived experience and so much of the work that’s been done qualitatively has been about the intensity and the constancy of that lived experience which you and I, for some reason just don’t see in the same way that we see chronic unremitting pain.

Alex: That’s very pointedly put.

Eric: So, can we jump to the article. Article will have links on our show notes, on our website GeriPal. If we look at this article published in Thorax looking at those regular low dose, sustained-release morphine-

Alex: 20 milligrams.

Eric: 20 milligrams result and improve breathlessness. And if I get the bottom line, there is no difference. So, should we throw… Oh, actually I’m not going to ask that question.

Alex: Yeah, we’re going to talk a little more about the study-

Eric: The study. What the heck did you do in this study before we get into the bottom line?

David: Well, we can go to the bottom line but look this was a multi-site study, it was a placebo-controlled study, it was still felt by the investigational review boards, Institutional review boards that the placebo was justified. But unfortunately they also insisted that as needed immediate release morphine solution was available to all participants, and that in itself is problematic and that was an IRB requirement. It wasn’t in the original design. The study had a primary endpoint at seven days and we believe that pharmacokinetically steady state is there by somewhere between 45 and 60 hours, but the pharmacodynamic effect with previously published is still having an impact perhaps five or six days after successful dose increment. That is that people’s breathlessness is continuing to improve after five or six days. By seven days we’re hoping that we’re in a state that is optimizing the reduction in people’s chronic breathlessness. It was otherwise a relatively straightforward study.

David: We measured the primary outcome as breathlessness now and we’ll return to that in a minute. We measured it on a visual analog scale with twice daily diaries for that, as well as worst best in average breathless over the previous 24 hours. This was a large study in fact, this study is larger than several of the meta-analysis that talk about which we’ve spoken today. It was a substantial piece of work and a huge commitment on behalf of pulmonologists, palliative care physicians, cardiac physicians and oncologists.

Eric: Can you say a little about the patient population, I mean how was breathlessness measured in order to enter the study and what sort of patients were these?

David: This study started with a population saying it doesn’t matter what the underlying etiology is, but if you have a Modified Medical Research Council scale of three or four you are eligible for the study. It’s important also to note that the study actually started as a three arm, parallel arm fixed study with OxyContin so extended release Oxycodone three times a day at an equivalent dose. That arm was truncated a little early because of recruitment challenges and that paper has been published separately and interestingly that Oxycodone paper is strongly negative in all the primary and secondary outcomes.

Eric: Strongly negative.

David: Strongly negative

Lynn: Just a quick question about what is a person with an mMRC of three or four look like?

David: Yeah, four is either housebound because of breathlessness or getting breathless dressing or undressing. Three is someone who is really not keeping up with peers or colleagues along the flat at what would otherwise be considered a reasonable pace. I mean these are people who are stopping every 50 or 100 yards, as they go about their life and you see those people in shopping centers they actually sit down and catch their breath and then, make their way another 100 yards before they sit down again, and so these people are really quite challenged by their breathlessness.

Eric: To increase recruitment, you started also getting some two’s in there, right? Of mMRC of two what’s that?

David: That’s people who are again functioning a little better, but they’re still getting breathless around activities of daily living that you and I would absolutely take for granted. That decision was made pragmatically by the investigators, the number with clinician rated Modified Medical Research Council scale to in the final paper was actually only 25. So, it’s a very small number across the board and so it’s interesting to think about the dilutional effect of immediate release morphine solution for both arms, and the potential dilutional effect of having people with a Modified Medical Research Council scale two.

Eric: Yeah, and then the primary outcome was breathlessness now, and that was like an average between days five and seven, from baseline to the average between five and seven. Is that right?

David: Yeah, look absolutely. What we didn’t standardize was what you had to be doing as now. Like all of these studies and it’s a big challenge and there’s the retrospective scope, but these studies is designed several years ahead of reporting and we in fact have designed and completed the next study on the basis of this study. In fact, it closed about five weeks ago and one of the first things we changed was the primary endpoint, because breathlessness now is not going to be a great reflection and we’ve seen work in the interim from Irene Higginson’s group at King’s College London, suggesting that worst breathlessness far more accurately reflects the lived experience, and we’re exploring that also statistically with the data from the study that we’re discussing today.

Eric: Let’s get into outcomes here and maybe we’ll start with the benefits, in terms of your primary outcome there was no difference between breathlessness now in the 20 milligrams sustained morphine daily versus placebo dose.

David: That’s correct.

Eric: And there was no difference in worse breathlessness, best breathlessness it was just nothing going on in terms of the benefits side of the equation.

David: I think you’ll be interested in the secondary analysis particularly around worst breathlessness. Every single measure there, all the patients those with Modified Medical Research Council scale three and four, those with Chronic Obstructive Pulmonary Disease, all the direction was strongly in favor of morphine over placebo.

Eric: Oh, okay.

David: The secondary analysis are going to be interesting and are going to be very informative for how we measure breathlessness. Daisy Janssen’s group in the Netherlands have also recently completed a study, I’m really excited to see the results of that, they built their primary outcome around the Chronic Obstructive Pulmonary Disease Assessment Tool, a CAD tool and it’s going to be fascinating. One of our challenges Is that if we’re shifting the threshold at which people get breathless, we may not see a change in their breathlessness scores. That’s one of the challenges in comparison to pain for example, if you relieve breathlessness so that people can do more, chances are they going to do as much as they used to, to induce the same level of breathlessness that was tolerable to them.

Lynn: Got it.

David: In our current study we’ve included Fitbit recordings in which one and three to try and understand where the step counts are actually changing, I have no idea we haven’t closed the data set. I haven’t seen it so I’m absolutely blind to those findings, but it’s absolutely in the design and conduct in the study. So, that we’re starting to measure some other things that can help us understand again the lived experience of chronic breathlessness.

Alex: Was there data on physical functioning in this paper? Like, did they do more? Do we have any of that outside of Fitbits?

David: We really don’t, and that’s why the next study had Fitbit measurement tools such as Karnofsky — a very broad brush tools to get the sort of differences that we expect in this patient population.

Lynn: If I’m understanding this right, you could have another study that measures worst breathlessness, and there might be no difference in the worst breathlessness however, they’re doing more?

David: That’s a potential outcome and if that’s the outcome, I’d be saying that’s a very positive outcome for populations that are just so challenged by their breathlessness. The other study which is in preparation is a pharmacogenomics study and we’ve got data on about 140 people for a pharmacogenomics study looking at responses, and clearly there are some people who are ultra responders with some particular single nucleotide polymorphism. That’s going to be an exciting paper that’s coming out in 2020.

Eric: Interesting, so we should be drawing the blood and maybe someday-

Lynn: Genotyping.

Eric: Right.

David: Well, I guess it’s not that far away.

Alex: Going back to this paper does this change anything? Because we were talking a lot about using instead of short acting long acting opioids, and one of the challenges here was that one group use short acting opioids and maybe that diluted to the fact that means short acting opioids have some role if there was a delusion of the fact.

Eric: Right

Alex: Does this paper argue that maybe it’s not that important whether it’s long acting or short acting opioids? Should this change our practice?

David: I think the bottom line here is that regular systemic opioids… and again specifically morphine is where we have the best evidence. I think we have very little evidence to talk to as needed, particularly as needed in some sort of acute exacerbation, but we do have good evidence that regular systemic morphine, reduces symptomatically chronic breathlessness in enough patient to warrant a careful clinical trial.

Eric: It sounds like maybe not in those patients who don’t have a lot of Dyspnea Baseline, but potentially for those who have more Dyspnea Baseline with a caveat is that we don’t know anything about their function and maybe there’s something more there. Is that right?

David: Yeah, absolutely. A study published several years ago showed people with more intense breathlessness were likely to develop more benefit from the commencing opioids in this setting so that’s not news to us. I think this reinforces this and I think the other thing it reinforces for us really importantly, we’re talking about a population that includes people who have not left their house simply because of breakfast. For many of us, particularly in hospital based practice rather than community based practice, that’s a population that’s largely invisible to us except in acute exacerbations, and even then they really want to try and avoid coming to hospital. That’s one in 300 people across our community, it’s a massive burden for every community in high income countries, and we had no idea what that’s like in low and middle income countries.

Alex: All right. Sticking with this issue of the short acting just for a moment, what Eric was alluding to earlier is that as you said, David both groups had access to short acting opioids is something like 2.5 milligrams of liquid morphine up to six times a day, and in the long acting group there was less use of the breakthrough medication compared to the short acting use. Although if you looked at it on a per day basis, it was like a half a dose difference in use, so it’s like less than two milligrams of a difference. A rather small difference overall and you argue in the discussion of this paper that future trials should not require access to short acting breakthrough medication for patients with breathlessness, and that is not an unethical position. Could you… I wonder if you could say more about that stance?

David: As you’ve already pointed out, our evidence base around immediate release morphine is actually far, far smaller than our evidence base around sustained-release morphine in this setting. This studies need to be done but particularly as needed. If we look at Stephen Simon’s work and look at the duration of acute exacerbations of breathlessness, by the time you give an as needed dose, and that dose is absorbed, metabolized and able to deliver some sort of symptomatic benefit. Most people’s acute breathlessness will have passed. That’s not what we’re trying to treat here, I think we need to make a really clear distinction between chronic breathlessness and acute on chronic breathlessness. And the person who doesn’t have a lot of background breathlessness but does become acutely breathless from time to time. As we think about that, this is about something that provides a background level to change the threshold at which people experience breathlessness. At the end of the day again, the question really becomes regular systemic morphine does have a role to play.

David: We need to do more studies and really understand what has needed immediate release solution or tablets actually can and can’t do, because I think the short answer is at the moment we just don’t know.

Lynn: And I think you are going to talk a little about morphine-

Alex: Wait, wait can you ask her again, we had some over feedback.

Lynn: You were going to talk about morphine versus other opioids. I know you mentioned the OxyContin piece.

David: Yeah, absolutely and so with regard to Oxycontin we have published the paper. It is the largest collection of people who have been on Oxycontin in a controlled clinical trial for chronic breathlessness, and this was strongly negative in every way we looked at the data in primary and secondary outcomes. And so, I think what we’re seeing there is a question mark, It reflects some earlier work Steve Oxberry’s paper on Breathlessness in Chronic Cardiac Failure, and so at the end of the day the first question that comes from that is, is there a class effect? And in short I think the answer is probably no and that we need to think really carefully about the additional work that needs to be done with other opioids in taking that observation forward. The other paper that we’ve published in the last 18 months is a feasibility trial looking at Coronary artery hypertension and chronic restlessness. And again, this study was not only negative every single measure and I went back to the people who did the randomization time and time again, every single measure favored placebo.

David: And so that then raises the question is all breathlessness equal? Does breathlessness from pulmonary arterial hypertension differ fundamentally from breathlessness in Chronic Obstructive Pulmonary Disease or interstitial lung disease or indeed cardiac failure or cancer? And so I think we’re actually to the point where we’re asking some really interesting questions that build on robust observations and ask us to really do more work.

Eric: It’s terrific, very exciting new directions and I love that we’re getting the early scoop on some of these. I wonder if you could talk a little bit about the harms in this study the people who received the long acting morphine had higher rates of constipation, nausea, fatigue sort of predictable consequences of taking long acting morphine, but you saw no signal of serious adverse events including death. What would you like to say to the listeners who are primarily clinicians, caring for people with breathlessness about the harms of opioid treatment?

David: So, importantly one of the great advantages of doing randomized trials like this is that you seek particular toxicities, particular harms, and so we’re especially interested in respiratory depression. We’re particularly interested in those that cause hospitalization or indeed as you say, death. Importantly, as with every other study that has not been seen, and that’s really important for practicing clinicians. We’ve extrapolated the person getting a stem dose of intravenous opioid following their hip fracture in the emergency department, to the use of regular sustained release morphine and they’re totally different. And so the good news is that despite looking forward reinforcing Daisy Janssen’s meta analysis, we have not seen respiratory depression and we have not seen respiratory compromise as a result of this. So, that’s really good news.

David: I think in terms of the other harms you’ve outlined them and yes they were expected. I think the other point to make from the paper which is important, is that the withdrawal rate and the pattern of those harms was earlier in the morphine arm than the placebo. And so yes, there are consequences for this and we’ve already suggested in previous work, but there’s actually quite a fine margin here between benefit and net benefit, and people saying, “Look, the net benefit isn’t worth continuing”. So, it is a matter of being very active in co-prescribing for constipation and ensuring that we’re asking people about nausea and that we’re working with them to minimize any of those harms.

Alex: So, co-prescribing for… We got a pause right there, there’s a feedback. Co-prescribing for constipation, you guys use Senna and Colace which I thought was interesting, due to lack of real evidence for Colace. Like what’s the… or docusate. What’s the rationale there?

David: Look, it was widespread standard practice, there’s no simple or right answer here and again I’m happy to do some studies from that space. There’s that great work of Katie Clark, which suggests we’ve totally underestimated the loss of pelvic floors, and we need to do much more work on understanding constipation and getting it right for our patients because at the moment hell we don’t.

Eric: Yeah, yeah. I wanted to ask, given in America we have only access to morphine 15 milligrams long acting sustained release, twice a day or Oxycontin long acting Oxycodone 10 milligrams twice a day, but anybody think of any other long acting low formulations that are relatively low dose?

Alex: … you’re not supposed to start with 12.

Lynn: Yeah, you’re not supposed to use that.

Eric: So, really our hands are tied, we do not have access to morphine 20 milligrams long acting or 10 milligrams long acting as you say. What can you say to our listeners who are saying, “Well, okay. You’re saying the evidence is not there for short acting, but we don’t have access to lower dose, long acting opioids as you’re using in your trials.”

Alex: Move to Australia.

Eric: And your patients-

David: We’d welcome you with open arms of course, but what I’ve said repeatedly is regular systemic morphine. If you don’t have it, you don’t have it, so you use regular immediate release solution. I think where we’re really lacking evidence is as needed use for immediate relief solutions.

Alex: So, start around the clock for example, what would be equivalent… 2.5 milligrams every four hours?

David: Yeah.

Alex: That’d be in the range. Right?

Eric: Yeah or start off with maybe a nighttime dose with some 2.5’s, I don’t know. It’s hard cause also don’t want them to wake up in the middle of the night every four hours-

Lynn: It would make them all very tired.

Alex: I see what you’re saying.

Eric: Yeah, that’s a challenge that we have here. Dave, I got another question for you I guess… Is it okay if I go a little off topic Alex from breathlessness? You’ve done some of the big seminal randomized controlled trials in palliative care, if you had to think of like…, you don’t have to talk about something you’re working on, but if like one, two or three interventions that you commonly see in palliative care where we really don’t have a lot of evidence, but man we need researchers to help answer that. Do you have like an idea in your mind? Like, besides dyspnea are there other things that you see as like we really need the evidence base for this? I guess constipation? We already mentioned that.

David: Yeah. Look, I think valve dysfunctioning including inoperable bowel obstruction, we don’t have a standard of care. We’re in the dark and can we say to patients and their families hand on heart, this intervention is going to make a predictable difference in X percent of people, very rarely can we say that. I think the other area on which we touched earlier in the podcast was that of delirium, there’s no doubt that delirium is a frequent visitor to our wards and to our patients in the community, we’re really not sure what we should be doing. That study had excess mortality in the intervention arm had prolonged delirium in the intervention arm compared to placebo [Alex: “with antipsychotics”]. Yeah, we really need to rethink what we’re trying to achieve there and how we achieve it, and I’m not sure that we have a standard of care.

David: It’s such a big problem not just in palliative care, and if we look to the studies in intensive care for example, we’re not seeing the benefits of anti psychotics in that setting either. So, we’re starting to get signal from several clinical disciplines that what we have assumed for 60 years was good practice and is now being challenged in inadequate trials. It is not only neutral, it may actually been having net harm and that’s very confronting to all of us. I’ve prescribed antipsychotics for years in delirium, and it’s very confronting for us to think, what have I been doing all these years when you see something that just has so many problems…

Eric: That’s why I love that study, because it actually showed that you give this medicine, you think it’s working because you see an improvement, but in truth if you believe the study they probably would have improved more if you actually didn’t do any of the pharmacological management. It also makes me think in that study there is, everybody got a non pharmacological management of their delirium. And I guess going back to dyspnea breathlessness was there that same thing in this study? Was there a non pharmacological management of dyspnea, and what is that like when we talk about that? What is that?

David: So, in this study to take the three step ladder that the Canadian Thoracic Society has for breathlessness, but reverse the reversible causes was absolutely part of the study. So, to enter the study the eligibility criteria reflected that very directly. In terms of the non pharmacological, those meta-analysis are being updated at the moment and the one systematic review will turn into four systematic reviews and I hope they’ll be out in 2020. We’ve got good evidence and large studies that suggest things like a walking frame, changes the engineering of the chest, and actually provides a real benefit for a lot of people.

Eric: Is a walking frame like a walker, like a four wheeled walker?

David: Yeah.

Eric: All right.

David: A walker, whatever we call them across the Atlantic or the Pacific, but yes the right concept. Breath training has a role but you need someone who’s very cognitively intact for that and the evidence is there’s kind of mid range for that. There are some things that are not in common practice, vibrating chest vest have an evidence base, I’ve never used them and I’m not sure that I’m going to be able to terribly easily, but people have tried that so it’s not a long list…

Eric: Are you believer in bedside fans?

David: Look, I’m I’m a fantastic believer in the small electric handheld fan, there’s no doubt about it and I was part of the multinational study that looked at that. We had people who essentially gave up their as needed salbutamol and just carried a fan with them. And we’ve seen evidence in the last few months coming out that time to recovery in people who had one of those tiny little dollar fans, time to recovery when they were breathless was decreased. And it also harks back in a way to the oxygen study that you mentioned earlier, that the administering medical air, that is air two liters a minute through nasal prongs was as effective, you couldn’t put a cigarette paper between the two arms of that study. And so there’s no doubt that air flowing has a very real effect and yeah, I’m a great fan of handheld battery operated fans.

Eric: Well, I really appreciate… There’s that feedback again. I really appreciate you being on the call with us and being on the podcast with us. I had a blast learning a lot from you.

Lynn: Yeah, I learned so much. I think I’m going to use some of this stuff this afternoon.

Eric: You’re going to use morphine this afternoon, Lynn?

Lynn: That didn’t come out quite right.

Alex: Thank you so much, David. I love it so much every time I talk with you, this has been incredible.

Eric: How about before we end Alex, can you give us a little bit more of-

Alex: Cakey bake? Here we go. [singing: “Every breath you take and every move you make, every bond you break, every step you take I’ll be watching you, and every single day and every word you say, every game you play every night you stay I’ll be watching you.”]

Eric: I’m trying to think of other ones, every corn you flake.

Alex: That’s cause you just had breakfast.

Eric: David again very big thanks for coming on-

Alex: Thank you so much.

Eric: We’ll have to have you back on once your next study gets published. But again, a very big thank you and thank you to all of our listeners.

Alex: And thank you to Archstone Foundation for funding us.

Eric: Goodbye, everybody.

Alex: Bye. Thank you.

Lynn: Bye.