Siri Leknes is a professor of social and affective neuroscience at the University of Oslo, Norway, and senior researcher at Oslo University Hospital. She completed her D.Phil. at Oxford, United Kingdom, and postdoctoral research at Gothenburg University, Sweden.
Professor Leknes’s work on the benefits of acute pain was awarded the Daniel M. Wegner Theoretical Innovation Prize in social and personality psychology. She has served as associate editor for Social Cognitive Affective Neuroscience and is now associate editor for Pain. She is also the president of the Society for Social Neuroscience.
Siri Leknes will present the Plenary Lecture, How opioids shape our feelings: sorting facts from myths at the 37th ECNP Congress on Monday 23 September 2024 in Milan, Italy. She recently spoke to ECNP Press Officer Tom Parkhill.
TP (Tom Parkhill): Professor Leknes, we’re looking forward to seeing you at the ECNP Congress in Milan – what will you be talking about?
SL (Siri Leknes): The talk will be on the lessons that I've learned from doing opioid research for the last 15 years, somewhat provocatively summarised as “opioids are overrated”. I’ll focus on how endogenous opioids and exogenous drugs affect the human experience of pain, stress and reward.
TP: Overrated is an interesting way of putting it. Obviously, opioids have been in the news over the last few years, especially in the USA. Do you mean in terms of the analgesic effects?
SL: Yes. Generally, both the public and the medical profession have the same expectation of opioids effects: to reduce pain, increase reward, and reduce stress. But the evidence does not really back that up terribly well. For sure, sometimes and in some people, opioids have these effects – but there is enormous variability. We see small and inconsistent effects of opioids on stress and reward in healthy non-opioid users. For pain, in head-to-head comparisons of an opioid with a non-opioid analgesic, or even analgesic combinations with and without opioids, the opioids are not actually better in most studies. This rather shocked me. What is better with opioids is that if you are struggling to manage a patient’s pain, you can just keep increasing the dose. In this sense, opioids are very powerful: it's useful to have a drug without an effective ceiling.
TP: A drug of the last resort?
SL: Yes. I think the field is definitely moving away from using opioids as a first line treatment in a lot of cases.
In our lab we study opioid use before, during and after surgery, and we study how opioids affect healthy people without pain in the lab. For opioid blockade, the simple answer is that not very much happens at all. The human brain is equipped with large amounts of opioid receptors; essentially they’re almost everywhere, with a very high density in the striatum and the thalamus. But if you give people a really large dose of an antagonist they might not even notice.
It appears to require special conditions for this system to kick in to a noticeable degree. You can stay in a perfectly good mood, you can still appreciate the people around you, and even your pain is often unaffected or only slightly worsened by opioid blockade. In our systematic reviews and meta-analyses, we see a small downward shift in reward appreciation and motivation, and a similarly modest increase in pain.
However, under some – as yet unknown – conditions, the endogenous opioids really do kick in. I keep thinking about 127 Hours, a movie about this guy who got stuck rock climbing and who had to hack off his own arm to survive. He describes feeling no pain at all when he hacks off his own arm. Obviously, we don't have experimental models of anything as extreme as that, but it's easy to imagine that endogenous opioids, along with presumably every other helping compound in the body, would be playing a major role in his situation.
I'm really curious about the highly variable and overall modest effects of opioid blockade on pain. I think if we can get a better handle on how the endogenous opium system works, that could help us use opioids wisely in in clinical settings.
We are also preparing a meta-analysis on the effects of endogenous opioids on feeling connected to other people. In summary, the effects are actually slightly larger than the pain-killing effects – although still small. I think that taking two effects together gives a pretty powerful message because everyone thinks “endogenous opioids, the body’s own pain-killing system” and then it turns out the literature actually supports at least as important a role for endogenous opioids in feeling bonded to people.
TP: The historical situation then is that clinicians are used to using opioids because they've always used opioids, and they need a reason to change. They need to have that type of mental step forward to actually look at other solutions for pain relief?
SL: A main take-home message from the pain literature is that ibuprofen and paracetamol are actually really good analgesics. Perhaps because they are readily available and they don't have any clear subjective effects, there is this assumption that they're not that effective. Especially in combination they work really well, however. If you have a molar extraction, paracetamol and ibuprofen will work at least as well as having a codeine paracetamol combination. There are so many RCTs showing this.
In one recent RCT on molar extraction, the authors write that the results in the literature didn't match their clinical experience, so they ran another RCT. And they found exactly the same as the other RCTs, which still doesn't match their clinical experience because they feel in their experience that the patients benefit from codeine. What I think might be happening is that some people really do benefit from codeine, but these individuals aren't representative, so they don't drive the group effects. And of course, in an RCT you are only looking at the group statistics.
TP: From a practical point of view, patients want opioids, I guess they apply pressure to clinicians to be prescribed opioids.
SL: Yes. I would want opioids too for severe pain, even knowing everything that that I do. My husband had surgery some years ago and was given a large package of tramadol. Unlike the hospital staff that prescribed them, I was very strict with him. I said, “you can only take those to sleep and only for the first three nights”. We need a change in attitudes, and crucially one of the things we really need is a shift in policies so that producers start making small packages.
One of the most dangerous things we do with opioids is to send people home with a packet of 20 or even 50 oxycodone pills when they need, maybe three, or eight, or none; some people really do need none. Some people have almost no pain after surgery, for instance. But we focus on this hypothetical ‘average’ patient that we're trying to cater to.
TP: My impression is that often doctors are focused on treating a condition, and that (rightly) takes their attention. Sometimes they are not able to give full attention to secondary effects like pain.
SL: I agree. And I really don't think that we should be blaming the clinicians. Clinicians are doing their best with the resources they have available. It’s not like they could spend two years to read up on the literature and figure out what's currently considered the best treatment for every single condition or symptom.
TP: So changing the packaging is one of the things which would help?
SL: Yes. And I think maybe some educational material on the efficacy of other analgesics would also help. In Norway the standard is that you're sent home from surgeries with just non-opioid combinations and then some rescue opioids.
But if you also provide patient information that most people do get excellent pain relief and excellent recovery with only these non-opioid medications, that would be encouraging because then you wouldn't feel so disappointed. You’re like “I’ve had surgery. You should give me some proper drugs, right? Where’s the morphine?”
TP: Education needs money to be put in, so really it’s the regulators and the health systems which need to drive this. You need basic education for that to manage people’s expectations.
SL: When I give talks on opioid effects, someone in the audience often protests and says, “oh, but I had opioids and they were amazing”. If that’s you, either you’re in this subgroup of people likely to enjoy opioids – or you just really love having your pain relieved. I certainly do: if I'm in a lot of pain, anything that takes my pain away, I'm going to be super excited about it.
TP: Any final thoughts?
SL: I think we as a field need to look into new ways of studying drug effects, because they are so variable between people and contexts. We need to identify subgroups or even home in on treatment effects at the individual level. Clinicians titrate drug doses all the time to optimise treatment, and I think we should start doing this in a systematic, double-blinded way, using single-case experimental designs (also known as N-of-1 studies). It would be extremely helpful to document the individual titration journeys to systematise all the knowledge that is out there in clinical practice.
TP: Thanks!
Siri Leknes, Norway, will speak on Monday 23 September at 10.20-11.05 CEST (Central European SummerTime).
PL03 — How opioids shape our feelings: sorting facts from myths
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