http://www.nature.com/news/strong-pl...TWT_NatureNews

Potential pain treatments are struggling to prove their worth over a rising placebo effect seen in US trials.

Jo Marchant
06 October 2015

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 data1 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 antipsychotics2, 3, 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 Pain1.

Only in America
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.

Larger, bigger US trials probably cost more, and the glamour and gloss of their presentation might indirectly enhance patients? expectations, Mogil speculates. Some larger US trials also use contract research organizations that can employ nurses who are dedicated to the trial patients, he adds ? giving patients a very different experience compared to those who take part in a small trial run by an academic lab, for instance, where research nurses may have many other responsibilities...