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The Mechanism of Placebo Analgesia 1978, Levine et al (Claims Proof of Placebo)

Discussion in 'Research methodology news and research' started by DigitalDrifter, Aug 20, 2023.

  1. DigitalDrifter

    DigitalDrifter Senior Member (Voting Rights)

    This much cited (over 1600 citations) study from 1978 claims to have proven the placebo effect is real.


    Hutan and Sean like this.
  2. Hutan

    Hutan Moderator Staff Member

    Aotearoa New Zealand
    So, a painful dental operation -
    Patients were told that they might receive either morphine ('a powerful analgesic'), placebo, or naloxone (which might increase their pain).

    There was blinded administration of naloxone and a placebo. It says that patients given morphine were excluded from the analysis of the results. Perhaps the reduction in pain from the placebo didn't match that of the morphine?

    (Re when the D1 and D2 administrations happened. The abstract says 3 and 4 hours after surgery. The Methods says 2 and 3 hours after the start of anaesthesia (for the operation).)

    Figure 1:
    Screen Shot 2023-08-21 at 1.26.32 pm.png
    This figure is just for participants given placebo first. The first dotted vertical line is D1 when both sets of participants are given the placebo. The second vertical dotted line is D2 when one group is given the placebo (black dots - 17) and the other is given the naloxone (empty dots- 23).
    Note that the administration of the first placebo at D1 didn't have much effect on the mean reports of pain. The trajectory of reports of pain seems very much in line with what was happening before D1. That trajectory continues for those given the placebo at D2, a slight increase in the mean. Those given the naloxone at D2 reported higher levels of pain.

    So, so far, the mean results are in entirely line with what we might expect from an inert drug and a drug that blocks endorphins.

    The authors then fish around in the data, identifying two groups among those given the placebo at D1 - a group who reported that their pain stayed the same or improved from just before D1 to just before D2. They called these people the 'placebo responders'. The 'placebo non-responders' were the people who reported that their pain worsened. Figure 2 is just for 23 people (the people were later given naloxone at D2). Figure 2 tells us that there were only 3 people in the placebo responders reporting an improvement of more than 2 on a scale of 1 to 10, whereas most people reported worsening pain (e.g. 10 people's reported that their pain increased by more than 2 points).

    Figure 3 is again just for the 23 people who got the placebo first and naloxone second. It plots the mean pain scores for the people classed as placebo responders and as placebo non-responders throughout the study.

    Screen Shot 2023-08-21 at 2.21.16 pm.png

    20 minutes after the placebo at D1, there isn't much difference between the groups. The difference in mean pain scores one hour after D1 for the two groups is just 2.5 points. And, remember, the grouping was done specifically to maximise the difference in pain scores. I think what we are seeing is probably some people assuming that they got the morphine at D1 and expecting an improvement, and more people assuming that they got the naloxone at D1 because the pain is worsening as they come off the anaesthetic. Indeed, it looks as though the pain trajectory before D1 has a lot to do with whether people reported increasing or decreasing pain. People who reported high pain levels after surgery were, at D1, less likely to report further increases in pain and more likely to report an improvement.

    I think it's worth noting that people had to mark on a line from 1 to 10 where their pain was, and they weren't able to see their previous reports. So, it was hard for people to calibrate the reporting.

    It's not a clean study, there are drop outs and data not reported, it's hard to know what the baseline pain is doing and there's the effect of residual pain control affecting assessments of pain trajectories. And it's not large. I don't think this study demonstrates that the placebo effect is anything more than an expectation effect.

    We know that endorphins are produced when there is pain. It's entirely reasonable to expect that people given a drug that blocks the receptors for those endorphins will report higher levels of pain, although the actual impact here looks to be relatively small and possibly also short-lived.
    I find it hard to believe that the whole hype of the therapeutic placebo is built on this study. I wonder if there have been later studies that present more convincing evidence. The asthma study is cleaner study of the placebo effect, and it found no real benefit. It's a much cleaner study - people with asthma given a biologically active drug, a placebo drug and nothing. People who were given either the drug or the placebo reported breathing easier, but only people given the biologically active drug actually had improved lung function.

    Happy to hear if I have missed something in the study. What are your thoughts @DigitalDrifter?
    Trish, Wonko, bobbler and 2 others like this.
  3. bobbler

    bobbler Senior Member (Voting Rights)

    More like the time-difference accounts for the placebos in the middle being the group where anything varied. Some of whom the initial anesthesia had worn off already, others who hadn't at 3hrs?

    "Patients given naloxone [at 3hrs, the first time point] reported significantly greater pain than those given placebo. Patients given placebo as their first drug was either placebo responders, whose pain was reduced or unchanged, or nonresponders whose pain increased.

    Naloxone given as a second drug [at 4hrs] produced no additional increase in pain levels in nonresponders but did increase pain levels of placebo responders. Nonresponders had a final mean pain rating identical to that of responders who received naloxone as their second drug."

    I've inserted the brackets to note the timings were only 1hr apart. THe obvious explanation for the one tiny bit these authors are claiming is 'the effect' seems to be that a small group were still feeling benefit from anesthesia at 3hrs and then 4hrs, but probably less than e.g. when they'd just been given said painkillers.

    You can rename them as nonresponders and responders all you like (this is insightful as the Heins et al, 2013 paper uses exactly these terms to post-hoc divide their groups) but really they gave people a sugar pill then asked how their pain was - and the very action of taking said pill would have involved swallowing at least a pill, probably with water over the very area where a back tooth had been extracted thereby for some potentially antagonising or twinging it or at least reminding them of said pain and others maybe it helped by washing the area or they managed to avoid the area.

    How do these people think what they did was forensic with that massive flaw? Why did they think choosing tooth extraction and then swallowing pills over them was a good context to choose? Have they never had a tooth extraction or tonsillectomy themselves? And were they too stupid to see that choosing something mouth-based when the apparent placebo is mouth-based might be 'confounding'?
    Wonko likes this.
  4. bobbler

    bobbler Senior Member (Voting Rights)

    Or were these given intravenously? I can't tell any of this from the abstract but it feels the only way it could have been blinded or done as a placebo.

    morphine is sour as heck and not in pill form. I don't know what form naloxone or the placebo they used was but I though naloxone (admittedly from TV programmes) was needle or nose spray and placebo tends to be a pill.

    If they were all done intravenously then it adds still another issue with their claims of pain that confound, because it isn't painless to push a drug that way for everyone - and when you are already in pain as anethetic is wearing off and you've been bashed about by a big tooth extraction then even more so?
    Hutan likes this.
  5. Hutan

    Hutan Moderator Staff Member

    Aotearoa New Zealand
    Yes, intravenously.
    Wonko and bobbler like this.

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