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bibliography * The PainScience Bibliography contains plain language summaries of thousands of scientific papers and others sources, like a specialized blog. This page is about a single scientific paper in the bibliography, Tuttle 2015.

Is the placebo effect getting stronger? The Tuttle kerfuffle

updated
Tuttle AH, Tohyama S, Ramsay T, Kimmelman J, Schweinhardt P, Bennett GJ, Mogil JS. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain. 2015 Dec;156(12):2616–26. PubMed #26307858.
Tags: medications, mind, chronic pain, scientific medicine, neurology, self-treatment, treatment, pain problems

PainSci summary of Tuttle 2015?This page is one of thousands in the PainScience.com bibliography. It is not a general article: it is focused on a single scientific paper, and it may provide only just enough context for the summary to make sense. Links to other papers and more general information are provided at the bottom of the page, as often as possible. ★★★★☆?4-star ratings are for bigger/better studies and reviews published in more prestigious journals, with only quibbles. Ratings are a highly subjective opinion, and subject to revision at any time. If you think this paper has been incorrectly rated, please let me know.

Tuttle et al. reported on a bizarre thing: placebo response in trials of pain-killers seems to be growing. This finding got a lot of attention, and generally added to placebo hype and mystique. But let’s be very clear that this study raised more questions than it answered, and probably the only implication you can take to the bank is that (Dr. Steven Novella) “it is yet more evidence that placebo effects are complicated and are largely due to artifacts in the way clinical trials are designed and executed.”

The data shows this phenomenon occurring in the US specifically, which could mean that placebo is growing in response to drug advertising and the impressive scale of trials conducted there (more impressed patients = more impressive placebos). That inflated placebo effect might be masking real analgesic effects: “There are a lot of people in the pain field who believe the drugs that are failing clinical trials actually work, it’s just that the trials can’t show it.”

And it could also just mean that the results of drug trials are changing as they get more complicated. In other words, science is tricky.

Sometimes meaningful analysis of papers is way above my pay grade. Here’s some selected perspectives from folks who really know their stuff:

Dr. Neil O’Connell:

Using the term ‘placebo responses’ to label something that represents much more impacts upon the way we interpret the results. Arguably the big challenge presented by the data in this review is not the size of the placebo ‘responses’ but the stagnation seen in the outcomes from the groups receiving the drugs. The benefit offered by our drugs is smaller than we thought and does not seem to be getting any better any time soon. Not quite as likely to make the news, but perhaps far more newsworthy.

Dr. Steven Novella:

If the change in the size of the placebo response is due to the way clinical trials are designed, is this a good thing or a bad thing? In other words, are trials showing less of a difference between treatment and placebo because they are getting better (implying that older studies were more false positive) or because they are getting worse (newer studies are more false negative)? This is a critical question.

And Dr. David Colquhoun seems to think the whole business is a tempest in a teapot (and he’s as authoritative on the subject of placebo as anyone has ever been):

I find the arguments in this piece quite baffling. If a treatment does not perform better than a dummy placebo, then it doesn't work. The trial is not thwarted by the placebo response: it has answered the question that was asked, even if the answer is a disappointing one. It is also not right to refer to responses that are observed in people who are given a dummy pill as a placebo response. The changes seen in the dummy group are a combination of placebo response and regression to the mean (roughly. the get-better-anyway effect). There is an increasing body of evidence that the latter is more important than the former. Placebo effects, though real, are generally too small in size to be of noticeable benefit to patients.

~ Paul Ingraham

original abstract

Recent failures of clinical trials of novel analgesics designed to treat neuropathic pain have led to much speculation about the underlying reasons. One oft-discussed possibility is that the placebo response in these trials has increased in recent years, leading to lower separation between the drug and placebo arms. Whether this has indeed occurred has not yet been adequately addressed. Here, we extracted data from published randomized controlled trials (RCTs) of drugs for the treatment of chronic neuropathic pain over the years 1990-2013. We find that placebo responses have increased considerably over this period, but drug responses have remained stable, leading to diminished treatment advantage. This trend has been driven by studies conducted in the U.S.A. Consideration of participant and study characteristics revealed that in the U.S.A. but not elsewhere, RCTs have increased in study size and length. These changes are associated with larger placebo response. Analysis of individual RCT time courses showed different kinetics for the treatment versus placebo responses, with the former evolving more quickly than the latter and plateauing, such that maximum treatment advantage was achieved within 4 weeks.

related content

Specifically regarding Tuttle 2015:

These two articles on PainScience.com cite Tuttle 2015 as a source:


This page is part of the PainScience BIBLIOGRAPHY, which contains plain language summaries of thousands of scientific papers & others sources. It’s like a highly specialized blog.