Clinical Research: Phase 1 - Phase 4

The Placebo Problem, Part 2: Rising Response

This is Part Two of our series on the increasingly high placebo response that is plaguing clinical trials in analgesia and psychiatry. Read the other parts here.

Analgesic and psychiatric drug development is facing an enormous problem: rising placebo responses in randomized controlled trials (RCTs) threaten the ability of pharmaceutical companies to successfully identify novel effective drugs. Even some older drugs like Prozac aren’t surpassing placebo anymore.

Up, up, up
While trials of other drug classes may also be similarly affected, the rising placebo effect has been well documented for three classes of drugs – painkillers, antidepressants, and antipsychotics – all of whom share a reliance on subjective, patient-reported outcome measures. The increasing placebo response among antidepressant and antipsychotic trials has been noted since at least the early 2000s, while a similar trend in analgesia has come to light more recently.

Several analyses of antidepressant trials have found that on average roughly one-third of adult patients in the placebo group exhibit a response (compared to half in the drug group), and this proportion is even greater in pediatric and adolescent trials. Among adults, the placebo response in antidepressant trials has grown by approximately seven percent each decade over the past 30 years.

Multiple analyses also demonstrate that antipsychotic trials in schizophrenia are experiencing a similar effect. Compared to baseline, improvements in several measures of symptom severity after six weeks have been found across time. For example, the placebo group’s average Positive and Negative Syndrome Scale (PANSS) score of schizophrenia symptoms, the most common metric used in clinical trials of the illness, improved by 10 points between 1993 and 2006.

A 2015 meta-analysis that examined 84 neuropathic pain RCTs conducted between 1990 and 2013 found that placebo responses in this therapeutic area have also increased dramatically, while drug responses have stayed the same. The end result is a greatly diminished drug advantage over placebo across time. While drugs produced nearly 30 percent more pain relief than placebos in 1996, by 2013 this margin of difference had decreased to a meager nine percent.

An American problem?
Surprisingly, the increase in placebo response observed in neuropathic pain was true only of trials conducted in the U.S.; placebo response rates in Europe and Asia remained similar across the 24 years examined in the meta-analysis. This is consistent with some (but not all) analyses of antipsychotic trials, which have also found worsening placebo responses in the U.S. but not elsewhere.

For both antidepressants and antipsychotics, a number of trial design factors such as an increased number of drug groups and larger sample size have been associated with the increasing placebo response. Two U.S.-specific trial characteristics seemed to be driving the increased placebo effect in neuropathic analgesics: size and length. Across time in the U.S, but not Europe or Asia, trials have become bigger, longer, and comprised of more study sites. In 1990, the average neuropathic pain trial enrolled fewer than 50 people and was four weeks long. By 2013, these statistics had jumped to more than 700 participants and a 12-week trial duration.

Increasing sample size and trial duration also predict a higher placebo response in analyses of osteoarthritis pain as well as chronic low back pain trials, although these studies did not assess the effect of geography. Interestingly, however, trial duration is associated with a lower placebo response in antipsychotic trials, underscoring the complexity of the placebo problem and its underlying causes.

Reasons for the rise
A number of reasons for the association of certain trial characteristics with the increasing placebo response have been proposed. A greater number of drug arms (and therefore a reduced probability of receiving placebo) likely increases patient expectancy of receiving the active drug, which in turn boosts the placebo response. Larger sample sizes, with the increased clinical support staff and other added resources they necessitate, may feel more official and legitimate to trial participants, and therefore also contribute to increased patient expectancy of pain relief.

Two possible mechanisms could account for the finding that placebo effect increases as trial length does. First, as patients experience some initial placebo analgesia, a positive feedback loop drives subsequent pain relief. Second, longer trials allow for more exposure to placebo response-boosting aspects of the treatment experience – for example, increased contact with clinicians, better education about disease management, and more social support.

Another possible explanation for the U.S.-specific increase in placebo response is that the U.S. is only one of two countries worldwide that allows direct-to-consumer (DTC) pharmaceutical advertising. The use of DTC television, print, and online ads has sky rocketed over the past several decades – American television viewers now watch an average of nine drug ads per day – leading to the hypothesis that this influx of information about powerful drug responses has increased patient expectations of pain reduction.

Although there are many reasons for the rising placebo response, patient expectations are clearly a major contributor. Keep reading the third installment of our Placebo Problem series, where we’ll discuss patient expectancy and other psychological mechanisms of the placebo response in more detail.