Thursday, October 8, 2015

Placebo 2

Drug companies have a problem: they are finding it ever harder to get painkillers through clinical trials. But this isn’t necessarily because the drugs are getting worse. An extensive analysis of trial data has found that responses to sham treatments have become stronger over time, making it harder to prove a drug’s advantage over placebo.

The change in reponse to placebo treatments for pain, discovered by researchers in Canada, holds true only for US clinical trials. “We were absolutely floored when we found out,” says Jeffrey Mogil, who directs the pain-genetics lab at McGill University in Montreal and led the analysis. Simply being in a US trial and receiving sham treatment now seems to relieve pain almost as effectively as many promising new drugs. Mogil thinks that as US trials get longer, larger and more expensive, they may be enhancing participants’ expectations of their effectiveness.

Stronger placebo responses have already been reported for trials of antidepressants and antipsychotics, triggering debate over whether growing placebo effects are seen in pain trials too. To find out, Mogil and his colleagues examined 84 clinical trials of drugs for the treatment of chronic neuropathic pain (pain which affects the nervous system) published between 1990 and 2013.

Based on patients’ ratings of their pain, the effect of trialled drugs in relieving symptoms stayed the same over the 23-year period—but placebo responses rose. In 1996, patients in clinical trials reported that drugs relieved their pain by 27% more than did a placebo. But by 2013, that gap had slipped to just 9%. The phenomenon is driven by 35 US trials; among trials in Europe, Asia and elsewhere, there was no significant change in placebo reponses.The analysis is in press in the journal Pain.

This effect would explain why drug companies have trouble getting new painkillers through trials, notes neuroscientist Fabrizio Benedetti, who studies placebo responses at the University of Turin, Italy. Over the past ten years, he says, more than 90% of potential drugs for treatment of neuropathic and cancer pain have failed at advanced phases of clinical trials.

But the finding that placebo responses are rising only in the United States is the most surprising aspect of the latest analysis. One possible explanation is that direct-to-consumer advertising for drugs—allowed only in the United States and New Zealand—has increased people’s expectations of the benefits of drugs, creating stronger placebo effects. But Mogil’s results hint at another factor. “Our data suggest that the longer a trial is and the bigger a trial is, the bigger the placebo is going to be,” he says...

Mogil’s data also challenge one of the fundamental principles of placebo-controlled trials—that comparing a drug against placebo tells us how well a drug works. A basic principle of these trials is that drug and placebo effects are additive: our total response to any drug we take is equal to the placebo response plus the drug’s biochemical effect. But Mogil found that although placebo responses have increased over time, drug responses haven’t risen by the same amount.

That suggests placebo and drug responses may not always be strictly additive. This isn’t entirely unexpected, Mogil argues, because both placebos and pharmaceutical painkillers tap into similar biological mechanisms—such as the release of endorphins in the brain. But if true, it suggests that growing placebo responses are masking real painkilling 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,” he says...

Mogil suggests it is also worth investigating the elements that generate the more powerful placebo response in US trials, and then incorporating those elements (such as the relationship between patient and nurse) into patient care. Ted Kaptchuk, director of placebo research at Harvard Medical School in Boston, Massachusetts, agrees. “If the major component of a drug in any particular condition is its placebo component, we need to develop non-pharmacological interventions as a first-line response,” he says.
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  1. 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 Aug 22. [Epub ahead of print]


    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.

  2. The Placebo Effect: History, Biology, and Ethics Patrick Lemoine, MD, PhD

    It took until 1785 to see the word "placebo" appear in the first medical dictionary, the Motherby's New Medical Dictionary, where it is defined as "a commonplace medication or method." The word "commonplace" should probably be taken to mean trite. Finally, in 1958, the word placebo appears officially in France in the seventeenth edition of Garnier and Delamarre's Dictionary of Technical Terms of Medicine and later in mainstream dictionaries. But it was only with the advent of double-blind controlled trials with random assignment that placebos gained scientific respectability. Up to that point, a sulfurous whiff of quackery hung around the word. The most recent research has also helped to understand how a state of mind, a suggestion, or an expectation on the part of the physician or the patient can induce objective and measurable changes.

    In a famous article gathering the data of 15 studies of 1082 patients with extremely varied pain, Beecher showed that a placebo analgesic is effective, on average, in 35.2% of cases, within the range of 4% and 86%. The pain that was the least organic (experimental pain triggered in a laboratory on healthy subjects) but also the least intense showed the weakest response to the placebo, while particularly distressful organic pain, like angina, proved to be most sensitive to placebo. Indeed, a major driver of the placebo effect is expectations: A healthy person who knows they are experiencing experimental pain that can be stopped whenever they want is surely less motivated to activate a "placebo strategy" than an ill person suffering from a more or less well-controlled but very worrying ailment.

    Since Beecher's article was published, many publications have quantified, in disease after disease, the effectiveness of the placebo and the importance of the placebo effect, depending on the patient's and the physician's psychological context. Other research has attempted to provide psychological, ethological, anthropological, or sociological explanations of its mechanisms of action, all based primarily on the suggestion, enthusiasm, and expectation of the doctor, who can induce the patient's reaction himself. Yet it is the biological interpretations that have shed the most unexpected—and convincing—light on this amazing phenomenon that, with the power of thought, can change parameters such as white blood cell count, cholesterol, gastric acidity, pupil size...and so on and so forth!...

    Our brain is the administrative headquarters of a formidable, unbelievable pharmaceutical company able to demand and distribute its products throughout our body. We manufacture multitudes of medications: antibiotics, antimitotics, painkillers, antipyretics, anxiolytics, antidepressants, anti-inflammatories, immunostimulants, anticholesterols, antihypertensives, antipsychotics, cancer drugs, and more. We can also activate other parallel circuits involving natural counterparts to more culturally and medically scandalous substances: anandamide (cannabis), alcohol, amphetamines, nicotine, cocaine, LSD, endorphins, and more. The president of this whole enterprise is "me"; our brains; each of us.